KR20160048758A - Method for producing spirooxindole derivative - Google Patents

Abstract

The present invention relates to a compound having a spirooxyindole skeleton, for example, a compound having an anti-tumor activity which has a spiroxyindole skeleton and inhibits the interaction of an Mdm2 protein and a p53 protein, or an intermediate thereof, And a method for manufacturing the same. A compound having an optically active 3-cyclic dyspyrroindole skeleton is efficiently obtained by carrying out a catalytic sub-1,3-dipole cyclization addition reaction using a subtitle ligand and a Lewis acid using ketimine as a reaction substrate.

Description

METHOD FOR PRODUCING SPIROOXINDOLE DERIVATIVE [0002]

The present invention relates to a process for preparing a pyrrolidine compound having a spirooxyindole structure.

A method for synthesizing a pyrrolidine compound having a cyclic spirooxyindole structure is to synthesize a pyrrolidine compound having a cyclic spirooxyindole structure in the presence or absence of a catalyst which promotes the reaction using aldehyde and an amine synthesized as a raw material as a reaction substrate, A method of synthesizing a racemic compound by a 3-dipole cyclization reaction is known (Non-Patent Document 1 - 4). The obtained racemic compound can be separated into a desired optically active substance by a chiral column using a technique such as HPLC or supercritical fluid chromatography (SFC).

As a stereoselective synthesis method of the above compound, a method of synthesizing a subtitle by a 1,3-dipole cyclization reaction using a chiral element has been reported (Non-Patent Documents 5 and 6). Furthermore, a method of producing a pyrrolidine compound having a cyclic 3-cyclopentyloxyindole structure by carrying out a 1,3-dipole addition reaction using a ketimine synthesized using an amine and a ketone as a reaction substrate has been reported (Patent Document 1).

On the other hand, as to the catalytic sub-synthesis of the above compound, catalytic sub-1,3-dipole cyclization reaction using aldimine as a reaction substrate has been extensively studied (Non-Patent Documents 7 to 18) There is no report on the synthesis of 3-cyclic dyspiroindole by ketimine as a reaction substrate.

WO2012 / 121361

 Jorgensen, K. A. et al, Org. Lett. 2005, 21, 4569  Jorgensen, K. A. et al, Chem. Rev. 1998, 98, 863  Grigg, R. et al, Tetrahedron, 1992, 48, 10431  Schreiber, S. L. et al, J. Am. Chem. Soc. 2003, 125, 10174  Carretero, J. C. et al, Tetrahedron, 2007, 63, 6587  Wang, S. et al, J. Am. Chem. Soc., 2005, 127, 10130  Wang, S. et al, J. Med. Chem. 2006, 49, 3432  Williams, R. M. et al, J. Am. Chem. Soc. 2000, 122, 5666  Gong, L.- Z. et al., J. Am. Chem. Soc., 2009, 131, 13819  Gong, L.- Z. et al., Org. Lett., 2011, 13, 2418  Gong, L.- Z. et al., Chem. Eur. J., 2012, 18, 6885  Waldmann, H. et al., Nat. Chem., 2010, 2, 735  Waldmann, H. et al, Tetrahedron, 2011, 67, 10195  Wang, C.-J. et al., Org. Biomol. Chem., 2011, 9, 1980  Arai, T. et al., Chem. Eur. J., 2012, 18, 8287  Amedohkouh, M. et al, Tetrahedron Asymmetry, 2005, 8, 1411  Cordova, A. et al, Chem. Comm. 2006, 460  Ma, J. A. et al, Org. Lett. 2007, 9, 923

The present invention relates to a compound having a spirooxyindole skeleton, for example, a compound having an anti-tumor activity which has a spiroxyindole skeleton and inhibits the interaction of an Mdm2 protein and a p53 protein, or an intermediate thereof, And a method for manufacturing the same.

As a result of intensive studies, the inventors of the present invention have found that by screening optimal reaction conditions for a sub-ligand and a Lewis acid serving as a center metal for promoting the catalytic sub-1,3-dipole cyclization reaction using ketimine as a reaction substrate, An efficient synthesis method of a compound having an active 3-cyclic dyspyrroindole skeleton has been established.

That is, the present invention relates to the following (1) to (20).

(1) a compound represented by formula (I):

[Chemical Formula 1]

A compound represented by formula (II):

(2)

And a compound represented by the formula (III):

(3)

Are reacted in a solvent using an asymmetric catalyst,

The compound represented by the formula (IV) or a salt thereof:

[Chemical Formula 4]

≪ / RTI >

[Of the formulas (I), (II), (III) and (IV)

R ¹ represents a hydrogen atom, a C ₁ -C ₆ alkylcarbonyl group which may have 1 to 3 substituents independently selected from the following group A, a C ₁ -C ₆ alkylcarbonyl group which may have 1 to 3 substituents independently selected from the following group A ₁ -C ₆ alkoxy group,

R ² represents a 5- or 6-membered heteroaryl group having 1 to 3 hetero atoms independently selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, a phenyl group, a C ₃ -C ₆ cycloalkyl group, or A C ₃ -C ₆ cycloalkenyl group,

The 5-atom or 6-atom heteroaryl group, the phenyl group, the C ₃ -C ₆ cycloalkyl group, and the C ₃ -C ₆ cycloalkenyl group may be substituted with a halogen atom, a vinyl group, an ethynyl group, a cyano group, a hydroxyl group , An amino group, a carboxyl group, an aminocarbonyl group, a C ₁ -C ₆ alkyl group which may have 1 to 3 substituents independently selected from the following A group, a C ₁ -C ₆ alkyl group which may have 1 to 3 substituents independently selected from the following A group ₃ -C ₄ cycloalkyl group, to which optionally a substituent selected independently have one of 1 to 3 in the a group C ₁ -C ₆ alkoxy group, C which may have to be 1 to 3 substituents selected independently one from the group a _A C ₃ -C ₄ cycloalkoxy group, a C ₁ -C ₆ alkylamino group which may have 1 to 3 substituents independently selected from the following group A, 1 to 3 substituents independently selected from the following group A A C ₁ -C ₆ alkylamino group which may be substituted, a saturated heterocyclic group of 4 to 7 atoms containing one nitrogen atom in the ring, which may have 1 to 3 substituents independently selected from the following group B, A C ₁ -C ₆ alkoxycarbonyl group which may have 1 to 3 substituents independently selected from the following group A, a C ₃ -C ₄ cycloalkoxycarbonyl group which may have 1 to 3 substituents independently selected from the following A group , A C ₁ -C ₆ alkylaminocarbonyl group which may have 1 to 3 substituents independently selected from the following group A, and C ₃ -C ₄ alkylcarbonyl optionally having 1 to 3 substituents independently selected from the group A May have 1 to 3 substituents independently selected from the group consisting of a cycloalkylaminocarbonyl group,

R ³ and R ⁴ each independently represent a C ₁ -C ₆ alkyl group which may have 1 to 3 substituents independently selected from the following group C, or

R ³ and R ⁴ may be combined to form a C ₄ -C ₆ cycloalkyl ring, a tetrahydrofuran ring, a tetrahydropyran ring, or a piperidine ring,

The C ₄ -C ₆ cycloalkyl ring, the tetrahydrofuran ring, the tetrahydropyran ring and the piperidine ring thereof may have 1 to 8 substituents independently selected from the following group D,

R ⁵ is a C ₁ -C ₆ alkoxy group which may have 1 to 3 substituents independently selected from the following group E, a C ₃ -C ₈ alkoxy group which may have 1 to 3 substituents independently selected from the following E group A cycloalkoxy group, a C ₂ -C ₆ alkenyloxy group, or -NR ⁵¹ R ⁵² ,

R ⁵¹ and R ⁵² each independently represent a hydrogen atom, a C ₁ -C ₆ alkyl group which may have 1 to 3 substituents independently selected from the following E group, 1 to 3 substituents independently selected from the following E group A C ₃ -C ₈ cycloalkyl group which may be present, or a hetero atom independently selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, which may have 1 to 3 substituents independently selected from the group E below, A saturated heterocyclic group having 3 to 6 atoms,

The ring Z is a benzene ring which may have 1 to 4 substituents independently selected from the following E group, a pyridine ring which may have 1 to 3 substituents independently selected from the following E group, Or a pyrimidine ring which may have 1 or 2 substituents selected from [

Group A: a halogen atom, a hydroxyl group, a C ₁ -C ₆ alkyl group, an amino group, a phenyl group

Group B: a C ₁ -C ₆ alkyl group, a hydroxyl group

Group C: a halogen atom, a hydroxyl group, a phenyl group, a pyridyl group,

Group D: a halogen atom, a C ₁ -C ₆ alkyl group optionally having 1 to 3 halogen atoms,

Group E: a halogen atom, a hydroxyl group, a vinyl group, an ethynyl group, a cyano group, C ₁ -C ₆ alkoxy group, an amino group, a halogen atom, a C ₁ -C ₆ alkyl group which may have one 1-3

(2) a compound represented by formula (I):

[Chemical Formula 5]

And a compound represented by the formula (V):

[Chemical Formula 6]

Are reacted in a solvent using an asymmetric catalyst,

The compound represented by the formula (IV) or a salt thereof:

(7)

≪ / RTI >

[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and Z are the same as defined in (1)],

(3) a catalyst in which an asymmetric catalyst is prepared from a Lewis acid and an aldehyde ligand,

(II) Lewis acid, Cu (I) Lewis acid, Cu (I) Lewis acid, Cu (II) ) ≪ / RTI > Lewis acid,

The sub-ligand has the following formula (VI):

[Chemical Formula 8]

A compound represented by the following formula (VII):

[Chemical Formula 9]

A compound represented by the following formula (VIII):

[Chemical formula 10]

A compound represented by the following formula (IX):

(11)

A compound represented by the following formula (X):

[Chemical Formula 12]

A compound represented by the following formula (XI):

[Chemical Formula 13]

And a compound represented by the following formula (XII):

[Chemical Formula 14]

(1) or (2), which is one kind of an asymmetric ligand selected from the group consisting of (1) and (2).

Among the formulas (VI), (VII), (VIII), (IX), (X), (XI)

R ⁶ represents a phenyl group which may have 1 to 3 substituents independently selected from the following group F,

The ring Y represents a benzene ring, a cyclohexane ring, or a dioxolane ring which may have 1 to 4 halogen atoms,

R ⁷ represents a phenyl group which may have 1 to 3 substituents independently selected from the following G groups or a furanyl group which may have 1 to 3 substituents independently selected from the group G below,

R ⁸ represents a hydrogen atom or a C ₁ -C ₆ alkoxy group,

R ⁹ represents a C ₁ -C ₆ alkoxy group, or

Two R ^{9 s} may be one to form a heterocyclic ring of 7 to 12 atoms containing two oxygen atoms in the ring,

X represents CH, CR < ¹⁰ > or a nitrogen atom,

R ¹⁰ represents a C ₁ -C ₆ alkoxy group,

V represents a phenyl group having one of P (R ¹¹ ) ₂ , PH (O) R ¹² , or P (R ¹¹ ) ₂ ,

R ¹¹ represents a C ₁ -C ₆ alkyl group, a cyclohexyl group, or a phenyl group which may have two trifluoromethyl groups,

R ¹² represents a C ₁ -C ₆ alkyl group or a phenyl group,

W represents a C ₁ -C ₆ alkylthio group, a dihydrooxazolyl group which may have one C ₁ -C ₆ alkyl group, CH (CH ₃ ) P (R ¹³ ) ₂ , or CHR ¹⁴ R ¹⁵ ,

R ¹³ represents a cyclohexyl group, a C ₁ -C ₆ alkyl group, or a phenyl group which may have 1 or 2 substituents independently selected from the group H below,

R ¹⁴ represents a phenyl group which may be substituted with one of P (R ¹⁶ ) ₂ ,

R ¹⁵ represents a C ₁ -C ₆ alkyl group or a di C ₁ -C ₆ alkylamino group,

R ¹⁶ represents a phenyl group or a cyclohexyl group,

U is to represents any one of ^a U to U ^d dog,

[Chemical Formula 15]

R ¹⁷ represents a phenyl group which may have 1 to 3 substituents independently selected from the following group F,

R ¹⁸ represents a C ₁ -C ₆ alkyl group or a phenyl group,

R ¹⁹ represents a hydrogen atom or a C ₁ -C ₆ alkyl group,

R ²⁰ and R ²¹ each independently represent a C ₁ -C ₆ alkyl group]

F group: a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group

G group: a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group, a di C ₁ -C ₆ alkylamino group

H group: a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkyl group which may have 3 halogen atoms

(4) The production method according to any one of (1) to (3), wherein the Lewis acid used in the preparation of the sub catalyst is Cu (I) Lewis acid or Cu (II) Lewis acid.

(5) acid Louis used in the preparation of the asymmetric catalyst, CuOAc, CuCl, CuBr, CuI , CuOTf, CuPF 6, CuBF 4, Cu (OAc) 2, Cu (OTf) 2, and is selected from the group consisting of CuSO ₄ The production method according to any one of (1) to (4), which is one kind of Lewis acid.

(6) The method for producing a catalyst according to any one of (1) to (6), wherein the sub-ligand used in the preparation of the sub-catalyst is at least one compound selected from the group consisting of the compound represented by the formula (V), the compound represented by the formula (VI) (1) to (5), which is one kind of an adduct ligand selected from the group consisting of the compound represented by the formula (IX), the compound represented by the formula (X) and the compound represented by the formula (XI) ≪ / RTI >

Among the formulas (V), (VI), (VII), (VIII), (IX), (X) and (XI)

R ⁶ represents a phenyl group which may have 1 to 3 substituents independently selected from the group consisting of a methyl group, a t-butyl group and a methoxy group,

The ring Y represents a benzene ring, a cyclohexane ring or a dioxolane ring,

R ⁷ represents a phenyl group or a furanyl group,

The phenyl group and the furanyl group may have 1 to 3 substituents independently selected from the group consisting of a methyl group, a t-butyl group, and a methoxy group,

R ⁸ represents a hydrogen atom or a methoxy group,

R ⁹ represents a methoxy group, or

Two R ^{9 s} may be one to form a 9-membered heterocyclic ring containing 2 oxygen atoms in the ring,

X represents CH, CR < ¹⁰ > or a nitrogen atom,

R < ¹⁰ > represents a methoxy group,

V represents P (R < ¹¹ >) ₂ ,

R ¹¹ represents a phenyl group which may have two trifluoromethyl groups,

W represents a dihydrooxazolyl group which may be substituted by a t-butylthio group, an isopropyl group, or CH (CH ₃ ) P (R ¹³ ) ₂ ,

R ¹³ represents a phenyl group which may have 1 or 2 methyl groups,

U represents U ^a or U ^d ,

R ¹⁷ represents a phenyl group,

R ¹⁸ represents an isopropyl group, a t-butyl group, or a phenyl group,

R < ¹⁹ > represents a hydrogen atom,

R ²⁰ and R ²¹ each independently represents a methyl group or a t-butyl group]

(7) The production method according to any one of (1) to (6), wherein the sub-ligand used in the preparation of the sub-catalyst is one kind of sub-ligand selected from the following.

[Chemical Formula 16]

[Chemical Formula 17]

(8) The process according to the above item (1), wherein the solvent used in the reaction is one or more solvents selected from the group consisting of N, N-dimethylacetamide, tetrahydrofuran, dimethoxyethane, 2-propanol, toluene, To (7).

(9) The production method according to any one of (1) to (8), wherein the compound or salt thereof to be produced has the following configuration.

[Chemical Formula 18]

Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and Z have the same meanings as defined in (1)

(10) The production process according to any one of (1) to (9), wherein R ¹ is a hydrogen atom.

(11) In the above formula (I)

The production process according to any one of (1) to (10), wherein the ring Z is a benzene ring which may have 1 to 4 halogen atoms.

(12) In the formula (II) or the formula (V)

The production method according to any one of (1) to (11), wherein R ² is a pyridyl group which may have 1 to 4 halogen atoms or a phenyl group which may have 1 to 5 halogen atoms.

(13) In the formula (II) or the formula (V)

R ³ and R ⁴ each represent a methyl group, or R ³ and R ⁴ are combined to form a cyclopentane ring, a cyclohexane ring or a tetrahydropyran ring,

(1) to (12), wherein the cyclopentane ring, the cyclohexane ring and the tetrahydropyran ring thereof may have 1 to 4 C ₁ -C ₆ alkyl groups on the ring.

(14) In the formula (III) or the formula (V)

Wherein R < ⁵ > is a substituent shown below,

[Chemical Formula 19]

(1) to (13).

(15) In the formula (III) or the formula (V)

The production method according to any one of (1) to (13), wherein R ⁵ is a C ₁ -C ₆ alkoxy group.

(16) A process for producing a compound, or a salt thereof, produced by using the production method described in (15)

To obtain a compound represented by the following formula (XIV) or a salt thereof:

[Chemical Formula 20]

And condensing the compound represented by NHR ²² R ²³ to obtain a compound represented by the following formula (XV) or a salt thereof:

[Chemical Formula 21]

≪ / RTI >

[Of the formulas (XIV) and (XV)

R ¹ , R ² , R ³ , R ⁴ and Z are the same as defined in any one of (1) to (13)

R ²² and R ²³ each independently represent a hydrogen atom, a C ₁ -C ₆ alkyl group which may have 1 to 3 substituents independently selected from the following Group I, 1 to 3 substituents independently selected from the following Group I A C ₁ -C ₆ alkylsulfonyl group which may be substituted, a C ₃ -C ₆ cycloalkyl group which may have 1 to 3 substituents independently selected from the following Group I, a substituent independently selected from the following Group I, A saturated heterocyclic group of 3 to 6 atoms having one hetero atom independently selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, which may be present in the ring, a substituent independently selected from the following Group I, A phenyl group which may have 1 to 3 substituents or a nitrogen atom which may have 1 to 3 substituents independently selected from the following Group I, And a sulfur atom, or a 5- or 6-membered heteroaryl group having 1 to 3 hetero atoms in the ring, or

R ²² and R ²³ may be combined to form a piperazine ring which may have 1 to 3 substituents independently selected from the following Group I]

Group I: a halogen atom, hydroxyl group, oxo group, carboxyl group, formyl group, amino group, amino group, cyano group, C ₁ -C ₆ alkylamino group, C ₁ -C ₆ alkylsulfonyl group, C ₁ -C ₆ alkylsulfonyl sulfonyl amide group, to C ₁ -C ₆ which may optionally have 1 to 3 substituents independently selected more C ₁ -C ₆ alkyl group, 1 to 3 have the substituents independently selected from the group J in the J group alkoxy group, a -C ₃ to C ₆ which may optionally have a substituent selected independently from one 1 to 3 C ₁ -C ₆ alkyl with from 1 to 3 substituents selected independently one from the group, to the group J in the J group A cycloalkylcarbonyl group, a C ₄ -C ₆ cycloalkyl group which may have 1 to 3 substituents independently selected from the following group J, a cycloalkyl group which may have 1 to 3 substituents independently selected from the following group J A C ₁ -C ₆ alkoxycarbonyl group, a piperidinyl group optionally having 1 to 3 substituents independently selected from the following group J, a pyrrolidinyl group optionally having 1 to 3 substituents independently selected from the following group J , A piperazinyl group optionally having 1 to 3 substituents independently selected from the following group J, a phenyl group or a tetrazolyl group optionally having 1 to 3 substituents independently selected from the following group J, An azetidinyl group which may have 1 to 3 substituents independently selected, a morpholino group which may optionally have 1 to 3 substituents independently selected from the following group J, a substituent independently selected from the following group J, A dihydropyrazolyl group which may have 3 or more oxadiazolyl groups

J group: a halogen atom, a hydroxyl group, an amino group, a carboxyl group, an aminocarbonyl group, a phenyl group, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkylamino group, a di C ₁ -C ₆ alkylamino group, a C ₁ -C ₆ alkylcarbonyl group , A C ₃ -C ₆ cycloalkyl group, a C ₁ -C ₆ alkylsulfonyl group, a C ₁ -C ₆ alkylsulfonylamide group

(17) a compound wherein R ²² represents a hydrogen atom,

R < ²³ > is a substituent shown below,

[Chemical Formula 22]

(16).

(18) A compound represented by the formula (XVI):

(23)

The compound represented by the formula (XVII):

≪ EMI ID =

And (XVIII): < EMI ID =

(25)

In a solvent:

Cu (I) Lewis acid, and Cu (II) Lewis acid, and a subgenus ligand selected from the following:

(26)

(27)

, ≪ / RTI >

The compound represented by the formula (XIX) or a salt thereof:

(28)

≪ / RTI >

[Of the formulas (XVI), (XVII), (XVIII) and (XIX)

M represents a nitrogen atom or CH,

L represents a single bond, an oxygen atom, CH ₂ or C (CH ₃ ) ₂ ,

R ⁵³ represents a C ₁ -C ₆ alkyl group]

(19) A compound represented by the formula (XVI):

[Chemical Formula 29]

And the compound represented by the formula (XX):

(30)

In a solvent:

Cu (I) Lewis acid, and Cu (II) Lewis acid, and a subgenus ligand selected from the following:

(31)

(32)

, ≪ / RTI >

The compound represented by the formula (XIX) or a salt thereof:

(33)

≪ / RTI >

[Of the formulas (XVI), (XX), and (XIX)

M, L, and R ⁵³ have the same meanings as defined in (19)

(20) A process for producing a compound or a salt thereof produced by using the production method described in (18) or (19)

To obtain a compound represented by the following formula (XXI) or a salt thereof:

(34)

And the following compounds:

(35)

To obtain a compound represented by the following formula (XXII) or a salt thereof:

(36)

≪ / RTI >

[Of the formulas (XXI) and (XXII),

M and L have the same meanings as defined in (18) or (19)

According to the present invention, a compound having a spirooxyindole skeleton, for example, a compound having an antitumor activity having a spiroxyindole skeleton and inhibiting the interaction of an Mdm2 protein and a p53 protein can be stereoselectively efficiently and inexpensively synthesized can do.

 In the present invention, the "halogen atom" is a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

In the present invention, the "C ₁ -C ₆ alkyl group" is a linear or branched chain alkyl group having 1 to 6 carbon atoms, and includes methyl, ethyl, propyl, isopropyl, butyl, isobutyl, , a t-butyl group, a pentyl group, an isopentyl group, a 2-methylbutyl group, a neopentyl group, a 1-ethylpropyl group, a hexyl group, an isohexyl group or a 4-methylpentyl group.

In the present invention, the "C ₃ -C ₆ cycloalkyl group" is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group.

In the present invention, the "C ₃ -C ₄ cycloalkyl group" is a cyclopropyl group or a cyclobutyl group.

In the present invention, the "C ₁ -C ₆ alkoxy group" means a group in which one C ₁ -C ₆ alkyl group is substituted with an oxy group, and a methoxy group, ethoxy group, propoxy group, isopropoxy group, Isobutoxy group, s-butoxy group, t-butoxy group, pentoxy group, isopentoxy group, 2-methylbutoxy group, hexyloxy group or isohexyloxy group.

In the present invention, the "C ₃ -C ₆ cycloalkoxy group" means a group in which one C ₃ -C ₆ cycloalkyl group is substituted with an oxy group, and a cyclopropoxy group, a cyclobutoxy group, a cyclopentyloxy group, Or a cyclohexyloxy group.

In the present invention, the "C ₃ -C ₄ cycloalkoxy group" is a cyclopropoxy group or a cyclobutoxy group.

In the present invention, the "C ₃ -C ₈ cycloalkoxy group" is a cyclopropoxy group, a cyclobutoxy group, a cyclopentyloxy group, a cyclohexyloxy group, a cycloheptyloxy group, or a cyclooctyloxy group.

In the present invention, the "C ₁ -C ₆ alkylthio group" means a group in which _one C ₁ -C ₆ alkyl group is substituted with a thio group. For example, a methylthio group, an ethylthio group, a propylthio group or an isopropylthio group.

In the present invention, the "C ₁ -C ₆ alkylsulfonyl group" means a group in which one of the above C ₁ -C ₆ alkyl groups is substituted with a sulfonyl group. For example, a methylsulfonyl group, an ethylsulfonyl group, a propylsulfonyl group, or an isopropylsulfonyl group.

In the present invention, the "C ₁ -C ₆ alkylsulfonylamide group" means a group in which one C ₁ -C ₆ alkylsulfonyl group is substituted with an amino group. For example, a methylsulfonylamide group, an ethylsulfonylamide group, a propylsulfonylamide group, or an isopropylsulfonylamide group.

In the present invention, the "C ₁ -C ₆ alkylcarbonyl group" means a group in which _one C ₁ -C ₆ alkyl group is substituted with a carbonyl group. For example, an acetyl group, an ethylcarbonyl group, a propylcarbonyl group, or an isopropylcarbonyl group.

In the present invention, the "C ₁ -C ₆ alkoxycarbonyl group" means a group in which _one C ₁ -C ₆ alkoxy group is substituted with a carbonyl group. For example, a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, or an isopropoxycarbonyl group.

In the present invention, the "C ₃ -C ₆ cycloalkylcarbonyl group" means a group in which one C ₃ -C ₆ cycloalkyl group is substituted with a carbonyl group, and includes a cyclopropylcarbonyl group, a cyclobutylcarbonyl group, a cyclopentylcarbonyl group, Hexylcarbonyl group.

In the present invention, the "C ₃ -C ₆ cycloalkoxycarbonyl group" means a group in which one C ₃ -C ₆ cycloalkoxy group is substituted with a carbonyl group, and a cyclopropoxycarbonyl group, a cyclobutoxycarbonyl group, a cyclopentyloxycarbonyl group , Or a cyclohexyloxycarbonyl group.

In the present invention, the "C ₁ -C ₆ alkylamino group" means a group in which _one C ₁ -C ₆ alkyl group is substituted with an amino group. For example, a methylamino group, an ethylamino group, a propylamino group, or an isopropylamino group.

In the present invention, the "di C ₁ -C ₆ alkylamino group" means a group in which two of the above-mentioned C ₁ -C ₆ alkyl groups which are the same or different are substituted with an amino group. For example, a dimethylamino group, a diethylamino group, a dipropylamino group, or a diisopropylamino group.

In the present invention, the "C ₁ -C ₆ alkylaminocarbonyl group" means a group in which one C ₁ -C ₆ alkylamino group is substituted with a carbonyl group. For example, a methylaminocarbonyl group, an ethylaminocarbonyl group, a propylaminocarbonyl group, or an isopropylaminocarbonyl group.

In the present invention, the "C ₃ -C ₆ cycloalkylaminocarbonyl group" means a group in which one C ₃ -C ₆ cycloalkyl group is bonded to the amino group side of the (-NH-C (═O) -) group , A cyclopropylaminocarbonyl group, a cyclobutylaminocarbonyl group, a cyclopentylaminocarbonyl group, or a cyclohexylaminocarbonyl group.

In the present invention, the "C ₃ -C ₈ cycloalkylamino group" means a group in which one C ₃ -C ₈ cycloalkyl group is bonded to the amino group, and is a cyclopropylamino group, a cyclobutylamino group, or a cyclopentylamino group.

In the present invention, the "C ₂ -C ₆ alkenyloxy group" means a group in which a straight-chain or branched-chain C ₂ -C ₆ alkenyl group having 2 to 6 carbon atoms is bonded to an oxy group. For example, a vinyloxy group, an allyloxy group, or an isopropenyloxy group.

In the present invention, the "C ₃ -C ₆ cycloalkenyl group" is a cyclopropenyl group, a cyclobutenyl group, a cyclopentenyl group, or a cyclohexenyl group.

In the present invention, the "5-atom or 6-member heteroaryl group" means a group containing 1 to 3 atoms other than carbon in the constituent atom of the ring, an atom selected independently from the group consisting of nitrogen atom, oxygen atom and sulfur atom Means a group derived from a monocyclic aromatic compound of 5 atoms or 6 atoms. Examples of the substituent include furanyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, pyridyl, pyrazyl, Or a pyridazinyl group.

In the present invention, "a saturated heterocyclic group having from 3 to 6 atoms" means a saturated heterocyclic group having from 3 to 6 carbon atoms which contains, in addition to carbon, a nitrogen atom, an oxygen atom and an atom selected from the group consisting of a sulfur atom Quot; means a group derived from a saturated cyclic compound of a monocyclic atom. For example, an aziridinyl group, an oxiranyl group, a thienyl group, an azetidyl group, an oxetanyl group, a thietanyl group, a pyrrolidinyl group, a tetrahydrofuranyl group, a tetrahydropyranyl group, a piperidinyl group, A tetrahydrothiopyranyl group, and the like.

In the present invention, the "sub catalyst" means a catalyst used in the synthesis of an adduct. For example, a catalyst having a metal atom in the catalyst.

In the present invention, " Lewis acid " means a substance capable of receiving an electron pair. For _{example, Zn (OTf) 2, AgOAc} , Cu (OTf) 2, CuOAc, Ni (OAc) 2, Co (OAc) 2, CuCl, CuBr, CuI, CuPF 6, CuBF 4, Cu (OAc) 2, Cu (OTf) ₂ , CuSO ₄ , and the like.

In the present invention, the term " subtitle ligand " means a substance having a subtitle and capable of coordinating with a metal, and includes not only a single-seated ligand but also a multi-ligand ligand. For example, it is possible to use a BINAP derivative, MeBIPHEP derivative, TunePHOS derivative, P-Phos derivative, JOSIPHOS derivative, Walphos derivative, FESULPHOS derivative, Taniaphos derivative, Jospophos derivative, FOXAP derivative, Mandyphos derivative, Ferrocelane derivative, PHOX derivative or QuinoxP derivative .

In the present invention, " having a subtitle " means having a subtitle center, a subtitle axis, or a subtitle face.

In the present invention, " * " means the subtitle center or subtitle axis.

In the present invention, "Cy" is an abbreviation of cyclopentyl group.

In the present invention, " ketimine " means an imine formed from a ketone and an amine, and is a compound having a structure in which the carbonyl group of the ketone is substituted by the nitrogen atom of the amine.

The compound represented by the formula (I), the compound represented by the formula (II), the compound represented by the formula (III), the compound represented by the formula (IV) (XI), a compound represented by formula (XII), a compound represented by formula (VII), a compound represented by formula (VIII), a compound represented by formula (IX), a compound represented by formula A compound represented by the formula (XIII) or a salt thereof, a compound represented by the formula (XIV) or a salt thereof, a compound represented by the formula (XV) or a salt thereof, a compound represented by the formula (XVI) , A compound represented by the formula (XVIII), a compound represented by the formula (XIX) or a salt thereof, a compound represented by the formula (XX), a compound represented by the formula (XXI) , All isomers (Dias An isomer, an isomer, a geometric isomer, a rotamer, etc.).

The compound represented by formula (I), the compound represented by formula (II), the compound represented by formula (III), the compound represented by formula (IV) or its salt, the compound represented by formula (V) , A compound represented by formula (VII), a compound represented by formula (VIII), a compound represented by formula (IX), a compound represented by formula (X), a compound represented by formula (XI) A compound represented by the formula (XIII) or a salt thereof, a compound represented by the formula (XIV) or a salt thereof, a compound represented by the formula (XV) or a salt thereof, a compound represented by the formula (XVI) (XXII), a compound represented by the formula (XIX) or a salt thereof, a compound represented by the formula (XX), a compound represented by the formula (XXI) or a salt thereof, and a compound represented by the formula , These isomers and All mixtures of the isomers are shown by a single formula. Therefore, the present invention includes all of these isomers and mixtures of any ratio of these isomers.

The compound represented by formula (IV), the compound represented by formula (XIII), the compound represented by formula (XIV), the compound represented by formula (XV), the compound represented by formula (XIX) , And the compound represented by the formula (XXII) can be converted into a salt by reacting with an acid in the case of having a basic group or by reacting with a base in the case of having an acidic group.

The salts based on basic groups include, for example, hydrohalide salts such as hydrofluoric acid, hydrochloride, hydrobromide and hydroiodide, inorganic acid salts such as nitrate, perchlorate, sulfate and phosphate, methanesulfonate, C ₁ -C ₆ alkylsulfonic acid salts such as methanesulfonic acid salts and ethanesulfonic acid salts, arylsulfonic acid salts such as benzenesulfonic acid salts and p-toluenesulfonic acid salts, carboxylates such as acetic acid salts, oxalic acid salts, tartaric acid salts and maleic acid salts .

Examples of the salts based on acidic groups include alkali metal salts such as sodium salts, potassium salts and lithium salts, alkaline earth metal salts such as calcium salts and magnesium salts, metal salts such as aluminum salts and iron salts; Salts of organic acids such as ammonium salts, t-octylamine salts, dibenzylamine salts, morpholine salts, glucosamine salts, phenylglycine alkyl ester salts, ethylenediamine salts, N-methylglucamine salts, guanidine salts, diethylamine salts, Ethylamine salt, dicyclohexylamine salt, N, N'-dibenzylethylenediamine salt, chloropropane salt, procaine salt, diethanolamine salt, N-benzylphenethylamine salt, piperazine salt, tetramethylammonium salt , Organic salts such as tris (hydroxymethyl) aminomethane salts; And amino acid salts such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamate salt, and aspartate salt.

The compound represented by the formula (IV) or a salt thereof, the compound represented by the formula (XIII) or a salt thereof, the compound represented by the formula (XIV) or a salt thereof, the compound represented by the formula (XV) (XXII), or a salt thereof, and a compound represented by the formula (XXII) or a salt thereof are left in the air or recrystallized, whereby water molecules are introduced into a hydrate And such hydrates are also included in the salt.

The compound represented by the formula (IV) or a salt thereof, the compound represented by the formula (XIII) or a salt thereof, the compound represented by the formula (XIV) or a salt thereof, the compound represented by the formula (XV) ) Or a salt thereof, a compound represented by the formula (XXI) or a salt thereof, and a compound represented by the formula (XXII) or a salt thereof are left in a solvent or recrystallized to absorb any kind of solvent, And the solvate is included in the salt.

Examples of the solvent include ether solvents such as tetrahydrofuran and 1,2-dimethoxyethane; alcohol solvents such as methanol, ethanol and 2-propanol; hydrocarbon solvents such as toluene; nitriles such as acetonitrile; Based solvent, an aliphatic ester-based solvent such as ethyl acetate or an amide-based solvent such as N, N-dimethylacetamide or N, N-dimethylformamide.

Next, preferred embodiments of the present invention will be described.

The compound represented by formula (I), the compound represented by formula (II), the compound represented by formula (IV), the compound represented by formula (V), the compound represented by formula (XIII) (XIV) and the compound represented by the formula (XV) are shown below.

R ¹ represents a hydrogen atom, a C ₁ -C ₆ alkylcarbonyl group, or a C ₁ -C ₆ alkoxycarbonyl group which may have one phenyl group. More preferably a hydrogen atom, an acetyl group, a t-butoxycarbonyl group, or a benzyloxycarbonyl group. More preferably, it is a hydrogen atom.

R ² represents a 5- or 6-membered heteroaryl group or phenyl group having 1 to 3 hetero atoms independently selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, and the five or six atom The heteroaryl group and the phenyl group thereof may have 1 to 3 substituents independently selected from the group consisting of a halogen atom, a hydroxyl group, an amino group, an aminocarbonyl group, and a C ₁ -C ₆ alkyl group.

More preferably a phenyl group which may have 1 to 3 halogen atoms or a pyridyl group which may have 1 to 3 halogen atoms. More preferably a phenyl group having one fluorine atom and one chlorine atom or a pyridyl group having one fluorine atom and one chlorine atom.

The ring Z is a benzene ring which may have 1 to 4 halogen atoms, and more preferably a benzene ring which has one chlorine atom.

R ³ and R ⁴ each independently represent a C ₁ -C ₆ alkyl group which may have 1 to 3 substituents independently selected from the group consisting of a halogen atom, a hydroxyl group and an amino group. More preferably, they are all the same C ₁ -C ₆ alkyl group. More preferably, all are methyl groups.

One of the aspect of the R ³ and R ^4, R ³ and R ⁴ is one, which may have 1 to 3 C ₁ -C ₆ alkyl group on the ring C ₃ -C ₆ cycloalkyl ring, on the ring one to three C ₁ -C ₆ is preferable to form a tetrahydropyran ring which may have one to three piperidine ring, or one to three C ₁ -C ₆ alkyl group on the ring which may have an alkyl group Do. A ring is formed, more preferably, on the ring with one to three C ₁ -C ₆ alkyl group a cycloalkyl which may have a pentane ring, a cycloalkyl which may have 1 to 3 C ₁ -C ₆ alkyl group on the ring A hexane ring, a tetrahydropyran ring which may have 1 to 3 C ₁ -C ₆ alkyl groups on the ring, more preferably a 4,4-dimethylcyclohexane ring.

R ⁵ is a C ₁ -C ₆ alkoxy group, a C ₃ -C ₈ cycloalkoxy group, a C ₂ -C ₆ alkenyloxy group, a C ₁ -C ₆ alkylamino group, a C ₃ -C ₈ cycloalkylamino group, or a tetrahydropyranyl group ≪ / RTI > More preferably a C ₁ -C ₆ alkoxy group or a tetrahydropyranylamino group, and more preferably a C ₁ -C ₆ alkoxy group.

R ²² and R ²³ each independently represent a hydrogen atom, a C ₁ -C ₆ alkyl group which may have 1 to 3 substituents independently selected from the following Group I, 1 to 3 substituents independently selected from the following Group I A C ₁ -C ₆ alkylsulfonyl group which may be substituted, a C ₃ -C ₆ cycloalkyl group which may have 1 to 3 substituents independently selected from the following Group I, a substituent independently selected from the following Group I, An azetidinyl group which may be optionally substituted, a pyrrolidinyl group which may have 1 to 3 substituents independently selected from the following Group I, a piperidinyl group which may have 1 to 3 substituents independently selected from the following Group I , A piperazinyl group which may have 1 to 3 substituents independently selected from the following Group I, a substituent independently selected from the following Group I is 1 A phenyl group which may have 1 to 3 substituents independently selected from the following Group I, a pyridyl group which may have 1 to 3 substituents independently selected from the following Group I, A pyrimidinyl group which may have 1 to 3 substituents independently selected from the group I, a pyridazinyl group which may have 1 to 3 substituents independently selected from the following Group I, A pyrrolyl group which may have 1 to 3 substituents, a pyrazolyl group which may have 1 to 3 substituents independently selected from the following Group I, a thiazolyl group which may have 1 to 3 substituents independently selected from the following Group I An imidazolyl group, an imidazolyl group which may have 1 to 3 substituents independently selected from the following Group I It represents a four pyridazinyl group, a group I to triazine which may have a substituent 1 to 3 substituents independently selected pieces may oxadiazolyl group, or to independently selected from the group I, which has one 1-3 in pyridazinyl.

Group I: a halogen atom, hydroxyl group, oxo group, carboxyl group, formyl group, amino group, amino group, cyano group, C ₁ -C ₆ alkylamino group, C ₁ -C ₆ alkylsulfonyl group, C ₁ -C ₆ alkylsulfonyl sulfonyl amide group, to C ₁ -C ₆ which may optionally have 1 to 3 substituents independently selected more C ₁ -C ₆ alkyl group, 1 to 3 have the substituents independently selected from the group J in the J group alkoxy group, a -C ₃ to C ₆ which may optionally have a substituent selected independently from one 1 to 3 C ₁ -C ₆ alkyl with from 1 to 3 substituents selected independently one from the group, to the group J in the J group A cycloalkylcarbonyl group, a C ₄ -C ₆ cycloalkyl group which may have 1 to 3 substituents independently selected from the following group J, a cycloalkyl group which may have 1 to 3 substituents independently selected from the following group J A C ₁ -C ₆ alkoxycarbonyl group, a piperidinyl group which may have 1 to 3 substituents independently selected from the following group J, a pyridinyl group which may have 1 to 3 substituents independently selected from the following group J, A piperazinyl group optionally having 1 to 3 substituents independently selected from the following group J, a phenyl group or a tetrazolyl group optionally having 1 to 3 substituents independently selected from the following group J, , A morpholyl group which may have 1 to 3 substituents independently selected from the following group J, a heterocyclic group which may have 1 to 3 substituents independently selected from the following group J, an azetidyl group which may have 1 to 3 substituents selected from A dihydropyrazolyl group which may be optionally substituted, an oxadiazolyl group

J group: a halogen atom, a hydroxyl group, an amino group, a carboxyl group, an aminocarbonyl group, a phenyl group, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkylamino group, a di C ₁ -C ₆ alkylamino group, a C ₁ -C ₆ alkylcarbonyl group , A C ₃ -C ₆ cycloalkyl group, a C ₁ -C ₆ alkylsulfonyl group, a C ₁ -C ₆ alkylsulfonylamide group

More preferably, R ²² and R ²³ each independently represent a hydrogen atom, a methyl group, a methylsulfonyl group, or any ^{one of the} following T ¹ to T ³⁵ .

[Formula 37-1]

[37-2]

M is a nitrogen atom or CH, and more preferably a nitrogen atom.

L is CH ₂ or C (CH ₃ ) ₂ , more preferably C (CH ₃ ) ₂ .

R ⁵³ is a C ₁ -C ₆ alkyl group.

A preferable combination of substituents of the compound represented by the formula (I) is a compound wherein R ¹ is a hydrogen atom, R ² is a phenyl group having one fluorine atom and one chlorine atom, and ring Z is a benzene group having one chlorine atom It is a ring.

A preferable combination of substituents of the compound represented by the formula (V) is that R ³ and R ⁴ form a 4,4-dimethylcyclohexane ring, and R ⁵ is a C ₁ -C ₆ alkoxy group.

In the present invention, preferred combinations of the substituents of the compound represented by the formula (IV) and the compound represented by the formula (XIII) are those in which R ¹ is a hydrogen atom and R ² is a phenyl group having one fluorine atom and one chlorine atom , Ring Z is a benzene ring having one chlorine atom, R ³ and R ⁴ form a 4,4-dimethylcyclohexane ring, and R ⁵ is a C ₁ -C ₆ alkoxy group.

A preferable combination of substituents of the compound represented by the formula (XIV) is a compound wherein R ¹ is a hydrogen atom, R ² is a phenyl group having one fluorine atom and one chlorine atom, and the ring Z is a benzene having one chlorine atom Ring, and R ³ and R ⁴ form a 4,4-dimethylcyclohexane ring.

The preferable combination of each substituent of the compound represented by the formula (XV) is a compound wherein R ¹ is a hydrogen atom, R ² is a phenyl group having one fluorine atom and one chlorine atom, and the ring Z has one chlorine atom Benzene ring, R ³ and R ⁴ form a 4,4-dimethylcyclohexane ring, and R ²² and R ²³ are the above-mentioned T ²⁴ .

The preferable combination of the respective substituents of the compound represented by the formula (XIX) is that M is a nitrogen atom, L is C (CH ₃ ) ₂ , and R ⁵³ is a C ₁ -C ₆ alkyl group.

A preferable combination of substituents of the compound represented by the formula (XX) is that L is C (CH ₃ ) ₂ and R ⁵³ is a C ₁ -C ₆ alkyl group.

A preferable combination of substituents of the compound represented by the formula (XXI) and the compound represented by the formula (XXII) is that M is a nitrogen atom and L is C (CH ₃ ) ₂ .

Next, the compound represented by formula (VI), the compound represented by formula (VII), the compound represented by formula (VIII), the compound represented by formula (IX), the compound represented by formula (X) (XII) will be described below.

The compound represented by the formula (VI) is a BINAP derivative, preferably a compound shown below.

(38)

More preferred are the compounds shown below.

[Chemical Formula 39]

The compound represented by the formula (VII) is a MeBIOPHEP derivative, a P-Phos derivative, and a TunePHOS derivative, and is preferably any of the compounds shown below.

(40)

(41)

More preferred are the compounds shown below.

(42)

The compound represented by the formula (VIII) is a JOSIPHOS derivative, a Walphos derivative, a FESULPHOS derivative, a Taniaphos derivative, a Jospophos derivative, or a FOXAP derivative, and is preferably any of the compounds shown below.

(43)

[Formula 44-1]

[44-2]

[Formula 45-1]

[Formula 45-2]

(46)

More preferred are the compounds shown below.

(47)

The compound represented by the formula (IX) is a Mandyphos derivative, and is preferably any of the compounds shown below.

(48)

The compound represented by the formula (X) is a ferrocelane derivative, and is preferably any of the compounds shown below.

[Formula 49-1]

[Formula 49-2]

The compound represented by the formula (XI) is a PHOX derivative, and is preferably any of the compounds shown below.

(50)

The compound represented by the formula (XII) is a QuinoxP derivative, preferably a compound shown below.

(51)

In the present invention, Lewis acid, CuOAc, CuCl, CuBr, CuI, CuOTf, CuPF _6, CuBF _4, Cu (OAc) _2, Cu (OTf) _2, or CuSO _4, and more preferably, the CuOAc, or Cu (OAc) ₂ .

In the present invention, the preferred combination of Lewis acid and an adduct ligand is CuOAc or Cu (OAc) _{2 as the} Lewis acid, and the following compound as the subtitle ligand.

(52)

(53)

In the present invention, the preferred solvent is 1 or 2 selected from the group consisting of N, N-dimethylacetamide, tetrahydrofuran, dimethoxyethane, 2-propanol, toluene and ethyl acetate. More preferably, it is one or two kinds selected from the group consisting of N, N-dimethylacetamide and ethyl acetate. The solvent may be mixed in an arbitrary ratio.

Next, the present invention will be described. The reaction conditions of the present invention should not be construed as limited to these. In the present invention, the functional group of the compound may be protected with an appropriate protecting group. Examples of such functional groups include a hydroxyl group, a carboxyl group and an amino group. The types of protecting groups and the conditions for introducing and removing the protecting groups are described, for example, in Protective Groups in Organic Synthesis (TW Green and PGM Wuts, John Wiley & Sons, Inc., New York, 2006).

[Recipe]

1) a method for producing a compound represented by the formula (IV)

(54)

The compound represented by the formula (IV) can be produced by reacting the compound represented by the formula (I) with the compound represented by the formula (II) and the compound represented by the formula (III) in the presence of a Lewis acid and a sub- . The compound represented by the formula (IV) can be prepared by previously producing the compound represented by the formula (V) (ketimine) from the compound represented by the formula (II) and the compound represented by the formula (III) With a compound represented by the formula (I).

The reaction is preferably carried out in the presence of a base.

The compound represented by formula (I) can be produced based on various documents. (For example, WO2006 / 091646, WO2012 / 121361, etc.).

The amount of the compound represented by formula (II) is in the range of 0.5 equivalents to 10 equivalents relative to the compound represented by formula (I), preferably 1.0 equivalents to 3.0 equivalents of the compound represented by formula (I) .

The amount of the compound represented by the formula (III) is in the range of 0.5 equivalents to 10 equivalents relative to the compound represented by the formula (I), preferably 1.0 equivalents to 3.0 equivalents of the compound represented by the formula (I) .

Lewis acids include, for example, Zn (II) Lewis acids, Ag (I) Lewis acids, Ni (II) Lewis acids, Co (II) used may be a Lewis acid such as, preferably, CuOAc, CuCl, CuBr, CuI , CuOTf, Cu (CH 3 CN) 4 PF 6, Cu (CH 3 CN) 4 BF 4, Cu (OAc) 2 a Cu (OTf) _2, or CuSO _4.

When the amount of the Lewis acid is in the range of 0.01 to 100 mol% with respect to the compound represented by the formula (I), the amount of the Lewis acid and the sub-ligand is preferably in the range of 0.8 to 3.0 equivalents of the Lewis acid, , When the Lewis acid is in the range of 0.5 to 20 mol% with respect to the compound (I), the ligand is preferably added in the range of 1.01 to 2.4 equivalents of the Lewis acid.

Subadjacent ligands include, for example, BINAP derivatives, MeBIPHEP derivatives, TunePHOS derivatives, P-Phos derivatives, JOSIPHOS derivatives, Walphos derivatives, FESULPHOS derivatives, Taniaphos derivatives, Jospophos derivatives, FOXAP derivatives, Mandyphos derivatives, Ferrocelane derivatives, PHOX derivatives, QuinoxP Derivatives, and preferably BINAP derivatives, Tunephos derivatives, MeBIPHEP derivatives, P-Phos derivatives, JOSIPHOS derivatives, FOXAP derivatives, FESULPHOS derivatives and the like.

Subsidiary ligands can be purchased from, for example, Aldrich, TCI, WAKO, STREM, and the like.

The base may, for example, be a tertiary amine such as triethylamine or N, N-diisopropylethylamine, an organic base such as sodium ethoxide or t-butoxy potassium, a sodium hydroxide, a sodium carbonate, And inorganic bases such as sodium acetate, potassium hydroxide, potassium carbonate, potassium hydrogencarbonate and potassium acetate. Preferred are tertiary amines such as triethylamine and N, N-diisopropylethylamine. Preferably, it is triethylamine.

The amount of the base to be used is in the range of 0.01 to 10 equivalents relative to the compound represented by the formula (I), preferably in the range of 0.01 to 0.2 equivalents relative to the compound represented by the formula (I).

Examples of the solvent include ethers such as tetrahydrofuran and 1,2-dimethoxyethane, alcohol solvents such as methanol, ethanol and 2-propanol, hydrocarbon solvents such as toluene, nitriles such as acetonitrile A solvent and an aliphatic ester solvent such as ethyl acetate or an amide solvent such as N, N-dimethylacetamide or N, N-dimethylformamide may be used alone or in an arbitrary ratio, , An ether type solvent such as tetrahydrofuran, an amide type solvent such as N, N-dimethylacetamide, and an aliphatic ester type solvent such as ethyl acetate may be used alone or in an arbitrary ratio.

The amount of the solvent to be used is in the range of 1 to 100 times the amount of the compound (I), preferably 5 to 50 times the amount of the compound represented by the formula (I), more preferably, To 8 times to 25 times the amount of the compound represented by formula (I).

The reaction temperature is in the range of -88 캜 to the boiling point of the solvent used, and preferably in the range of -20 캜 to 60 캜.

The reaction time is in the range of 30 minutes to 96 hours, preferably in the range of 30 minutes to 64 hours, and more preferably in the range of 30 minutes to 48 hours.

2) a method for producing a compound represented by the formula (XIV)

(55)

The compound represented by the formula (XIV) is obtained by hydrolyzing the compound represented by the formula (IV) (when R ⁵ is not -NR ⁵¹ R ⁵² ).

Hydrolysis can be carried out by adding a base or an acid in a solvent.

The base can be, for example, an organic base such as sodium ethoxide or t-butoxy potassium, an inorganic base such as sodium hydroxide, lithium hydroxide, sodium carbonate, potassium hydroxide or potassium carbonate, Sodium hydroxide, lithium hydroxide and potassium hydroxide, and more preferably sodium hydroxide.

The amount of the base to be used is in the range of 1 to 10 equivalents relative to the compound represented by the formula (IV), preferably in the range of 1 to 5 equivalents relative to the compound represented by the formula (IV) Is in the range of 1 to 3 equivalents relative to the compound represented by the formula (IV).

The acid can be, for example, hydrohalic acid such as hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, inorganic acids such as nitric acid, perchloric acid, sulfuric acid, phosphoric acid, C ₁ -C ₆ such as methanesulfonic acid, trifluoromethanesulfonic acid, Carboxylic acids such as acetic acid, trifluoroacetic acid, oxalic acid, tartaric acid and maleic acid, and preferably trifluoroacetic acid and hydrochloric acid. Examples of the carboxylic acid include acetic acid, trifluoroacetic acid, oxalic acid, tartaric acid and maleic acid.

The amount of the acid to be used is in the range of 1 to 100 equivalents relative to the compound represented by the formula (IV), preferably 1 to 10 equivalents relative to the compound represented by the formula (IV).

Examples of the solvent include ethers such as tetrahydrofuran and 1,2-dimethoxyethane, alcohol solvents such as methanol, ethanol and 2-propanol, hydrocarbon solvents such as toluene, nitriles such as acetonitrile Solvents and aliphatic ester solvents such as ethyl acetate, amide solvents such as N, N-dimethylacetamide and N, N-dimethylformamide, halogen solvents such as dichloromethane and chloroform, . Preferably, a mixed solvent of a halogen-based solvent such as dichloromethane, an alcohol-based solvent such as methanol, an ether-based solvent such as tetrahydrofuran, and an alcohol-based solvent such as methanol is preferable.

The amount of the solvent used is in the range of 1 to 100 times the amount of the compound represented by the formula (IV), preferably in the range of 5 to 50 times the amount of the compound represented by the formula (IV) To the compound represented by the formula (IV).

The reaction temperature is in the range of -88 캜 to the boiling point of the solvent used, and preferably in the range of -20 캜 to 60 캜.

The reaction time is in the range of 30 minutes to 96 hours, preferably in the range of 30 minutes to 64 hours, and more preferably in the range of 30 minutes to 48 hours.

3) a method for producing a compound represented by the formula (XV)

(56)

The compound represented by the formula (XV) is obtained by condensing a compound represented by the formula (XIV) and an amine, NHR ²² R ²³ , in a solvent with a condensing agent. Amines can be prepared on the basis of various documents. (For example, WO2006 / 091646, WO2012 / 121361, etc.).

The amount of the amine to be used is in the range of 0.5 equivalents to 10 equivalents relative to the compound represented by the formula (XIV), preferably 1.0 equivalents to 2.0 equivalents of the compound represented by the formula (XIV).

Condensers include, for example, azodicarboxylic acid di-lower alkyl ester-triphenylphosphines such as azodicarboxylic acid diethyl ester-triphenylphosphine, N, N'-dicyclohexylcarbodiimide (DCC) Carbodiimide derivatives such as 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDCI), 2-halo-1-lower alkylpyridinium Diarylphosphoryl azides such as diphenylphosphoryl azide (DPPA), phosphoryl chlorides such as diethylphosphoryl chloride, imidazole derivatives such as N, N'-carbodiimidazole (CDI) , Benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate (BOP), O- (benzotriazol-1-yl) -N, N, N ' (HBTU), O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluoro Benzotriazole derivatives such as hexafluorophosphate (HATU), (1H-benzotriazol-1-yloxy) tripyrrolidinophosphonium hexafluorophosphate (PyBOP) and the like, 4- (4,6-dimethoxy- , 3,5-triazin-2-yl) -4-methylmorphonium chloride (DM-TMM). Preferable examples of the compound represented by the general formula (I) include 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDCI), O- (benzotriazol- (HBTU), O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate (HATU) 1-yloxy) tripyrrolidinophosphonium hexafluorophosphate (PyBOP), diphenylphosphoryl azide (DPPA), 4- (4,6-dimethoxy-1,3,5-triazine- 2-yl) -4-methylmorphonium chloride (DM-TMM).

The amount of the condensing agent to be used is in the range of 1 to 10 equivalents relative to the compound represented by the formula (XIV), preferably in the range of 1 to 5 equivalents relative to the compound represented by the formula (XIV) , And the compound represented by the formula (XIV).

Examples of the solvent include ethers such as tetrahydrofuran and 1,2-dimethoxyethane, alcohol solvents such as methanol, ethanol and 2-propanol, hydrocarbon solvents such as toluene, nitriles such as acetonitrile A solvent and an aliphatic ester solvent such as ethyl acetate or an amide solvent such as N, N-dimethylacetamide and N, N-dimethylformamide can be used, and N, N-dimethylacetamide Amide-based solvents are preferable.

The amount of the solvent to be used is in the range of 1 to 100 times the amount of the compound represented by the formula (XIV), preferably 3 to 50 times the amount of the compound of the formula (XIV) To the compound represented by the formula (XIV).

The reaction temperature is in the range of -88 占 폚 to the boiling point of the solvent used, and preferably in the range of -20 占 폚 to 60 占 폚.

The reaction time is in the range of 30 minutes to 96 hours, preferably in the range of 30 minutes to 64 hours, and more preferably in the range of 30 minutes to 48 hours.

Example

Hereinafter, the present invention will be described in more detail by way of examples, but the scope of the present invention is not limited thereto.

The abbreviations used in the examples have the following significance.

Mg: milligram, g: gram, ml: milliliter, l: liter, MHz: megahertz.

In the following examples, the nuclear magnetic resonance (hereinafter, referred to as ¹ H NMR: 500 MHz) spectrum is defined as tetramethylsilane as a standard material and the chemical shift value as a value (ppm). The fragmentation pattern is represented by s, singlet, d, triplet, q, m and broad, respectively. As the "UHPLC" or "ultra-high speed liquid chromatography" in this embodiment, Prominence UFLC (Shimadzu Corporation) was used.

[Example 1]

(3'R, 4'S, 5'R) -6 "-chloro-4 '- (3-chloro-2-fluorophenyl) -2" Pyrrolo [cyclohexane-1,2'-pyrrolidin-3 ', 3 "-indole] -5'-carboxylate

(57)

(3E / Z) -6-chloro-3- (3-chloro-2-fluorobenzylidene) -1,3-dihydro-2H-indol- Cyclohexanone (50.4 L, 0.49 mmol), glycine ethyl ester (39.6 mg, 0.32 mmol), (R) -BINAP (12.1 mg, 0.019 mmol) and CuOAc N, N-dimethylacetamide (2.0 mL) of triethylamine (6.8 L, 0.049 mmol) was added to the solution, and the mixture was stirred at room temperature for 40 hours.

Ethyl acetate (2 ml), water (1 ml) and 20% aqueous ammonium chloride solution (1 ml) were added to the reaction mixture and vigorously stirred to separate the organic layer. The aqueous layer was extracted twice with ethyl acetate (2 ml each), and the organic layers were combined and washed three times with water (5 ml each). The obtained organic layer was concentrated under reduced pressure, ethyl acetate (6 ml) and silica gel (500 mg) were added to the residue, and the silica gel was separated by filtration. The filtrate was concentrated under reduced pressure, ethanol (1.25 ml) was added to the residue, water (1 ml) was added dropwise, and the mixture was stirred at room temperature overnight. The precipitated solid was filtered and dried under reduced pressure at 40 ° C to obtain the title compound (102.9 mg, yield 65%, 91% ee) as a solid.

(High performance liquid chromatography (HPLC) conditions for optical purity measurement)

Column: CHIRALPAK IC 4.6 × 250 mm, 5 μm

Mobile layer: 10 mM AcOH buffer: MeCN = 40: 60

Flow rate: 1.0 min / min

Column temperature: 40 DEG C

Detection wavelength: 254 nm

Injection volume: 5 μl

Holding time: The indicated compound = 14.1 min, Enantiomer = 11.4 min

[Example 2]

Chloro-4 '- (3-chloro-2-fluorophenyl) -4,4-dimethyl-2 " 2 ' -dihydrodipyrro [cyclohexane-l, 2 ' -pyrrolidin-3 ', 3 " -indole] -5 '

(58)

(3E / Z) -6-chloro-3- (3-chloro-2-fluorobenzylidene) -1,3-dihydro-2H-indol-2-one (WO2006 / 091646) 4-dimethylcyclohexanone (61.4 mg, 0.48 mmol), glycine ethyl ester (0.04 mmol), and triethylamine were added to a mixture of (R) -BINAP (12.1 mg, 0.019 mmol) and CuOAc (2.0 mg, 39.5 μL, 0.39 mmol) and triethylamine (6.8 μL, 0.049 mmol) in N, N-dimethylacetamide (2.0 mL), and the mixture was stirred at room temperature for 22 hours. Ethyl acetate (2 ml), water (1 ml) and 20% aqueous ammonium chloride solution (1 ml) were added to the reaction mixture and vigorously stirred to separate the organic layer. The aqueous layer was extracted twice with ethyl acetate (2 ml each), and the organic layers were combined and washed three times with water (5 ml each). The obtained organic layer was concentrated under reduced pressure, ethyl acetate (6 ml) and silica gel (500 mg) were added to the residue, and the silica gel was separated by filtration. The filtrate was concentrated under reduced pressure, ethanol (1.0 ml) was added to the residue, water (1 ml) was added dropwise, and the mixture was stirred overnight at room temperature. The precipitated solid was filtered and dried under reduced pressure at 40 ° C to obtain the title compound (137 mg, yield 82%, 94% ee) as a solid.

(HPLC conditions for optical purity measurement)

Column: CHIRALPAK OD-3R 4.6 × 150 mm, 3 μm

Moving bed: 10 mM phosphate buffer: MeCN = 40: 60

Flow rate: 1.0 min / min

Column temperature: 40 DEG C

Detection wavelength: 254 nm

Injection volume: 5 μl

Holding time: The indicated compound = 13.8 min, Enantiomer = 12.9 min

[Example 3]

Chloro-4'- (2-chloro-3-fluoropyridin-4-yl) -2 " -oxo-1 ", 2 ' '- dihydrodipyrrolo [cyclohexane-1,2'-pyrrolidin-3', 3 "-indole] -5'-carboxylate

[Chemical Formula 59]

(3E / Z) -6-chloro-3- [(2-chloro-3-fluoropyridin-4-yl) methylene] -1,3-dihydro-2H-indol- Cyclohexanone (50.4 L, 0.49 mmol), glycine ethyl (2-ethylhexyl) amide) was added to a mixture of (R) -BINAP (12.1 mg, 0.019 mmol) and CuOAc N, N-dimethylacetamide (2.0 mL) solution of ester (39.6 L, 0.39 mmol) and triethylamine (6.8 L, 0.049 mmol) was added and the mixture was stirred at 0 占 폚 for 18 hours. Ethyl acetate (2 ml), water (1 ml) and 20% aqueous ammonium chloride solution (1 ml) were added to the reaction mixture and vigorously stirred to separate the organic layer. The aqueous layer was extracted twice with ethyl acetate (2 ml each), and the organic layers were combined and washed three times with water (5 ml each). The obtained organic layer was concentrated under reduced pressure and purified from silica gel chromatography [heptane: ethyl acetate = 1: 1 (v / v)]. Ethanol (1.0 ml) was added to the obtained residue, water (1 ml) was added dropwise, and the mixture was stirred at room temperature overnight. The precipitated solid was filtered and dried under reduced pressure at 40 ° C to obtain the title compound (101.2 mg, yield 64%, 99% ee) as a solid.

(HPLC conditions for optical purity measurement)

Column: CHIRALPAK OD-3R 4.6 × 150 mm, 3 μm

Moving bed: 10 mM phosphate buffer: MeCN = 40: 60

Flow rate: 1.0 min / min

Column temperature: 40 DEG C

Detection wavelength: 254 nm

Injection volume: 5 μl

Retention time: The indicated compound = 7.7 min, Enantiomer = 8.7 min

[Example 4]

Chloro-4 '- (2-chloro-3-fluoropyridin-4-yl) -4,4-dimethyl- 1 ", 2" -dihydrodipyrro [cyclohexane-1,2'-pyrrolidin-3 ', 3 "-indole] -5'-carboxylate

(60)

(3E / Z) -6-chloro-3- [(2-chloro-3-fluoropyridin-4-yl) methylene] -1,3-dihydro-2H-indol- To a mixture of (R) -BINAP (12.1 mg, 0.019 mmol) and CuOAc (2.0 mg, 0.016 mmol), 4,4-dimethylcyclohexanone (61.4 mg, 0.48 mmol, N, N-dimethylacetamide (2.0 ml) of glycine ethyl ester (39.5 占,, 0.39 mmol) and triethylamine (6.8 占,, 0.049 mmol) was added and the mixture was stirred at 0 占 폚 for 14 hours. Ethyl acetate (2 ml), water (1 ml) and 20% aqueous ammonium chloride solution (1 ml) were added to the reaction mixture and vigorously stirred to separate the organic layer. The aqueous layer was extracted twice with ethyl acetate (2 ml each), and the organic layers were combined and washed three times with water (5 ml each). The obtained organic layer was concentrated under reduced pressure, ethyl acetate (6 ml) and silica gel (500 mg) were added to the residue, and the silica gel was separated by filtration. The filtrate was concentrated under reduced pressure, ethanol (1.0 ml) was added to the residue, water (1 ml) was added dropwise, and the mixture was stirred at room temperature overnight. The precipitated solid was filtered and dried under reduced pressure at 40 ° C to obtain the title compound (134.9 mg, yield 80%, 99% ee) as a solid.

(HPLC conditions for optical purity measurement)

Column: CHIRALPAK OD-3R 4.6 × 150 mm, 3 μm

Moving bed: 10 mM phosphate buffer: MeCN = 40: 60

Flow rate: 1.0 min / min

Column temperature: 40 DEG C

Detection wavelength: 254 nm

Injection volume: 5 μl

Holding time: The indicated compound = 9.4 min, Enantiomer = 10.5 min

[Example 5]

(3'R, 4'S, 5'R) -6-chloro-4 '- (3-chloro-2- fluorophenyl) -3', 3'-dimethyl- Spiro [indole-3,3'-pyrrolidine] -5'-carboxylate

(61)

(3E / Z) -6-chloro-3- (3-chloro-2-fluorobenzylidene) -1,3-dihydro-2H-indol-2-one (WO2006 / 091646) (23.8 L, 0.32 mmol), glycine ethyl ester (26.4 [mu] L, 0.15 mmol) was added to a mixture of (R) -BINAP (6.1 mg, 0.01 mmol), CuOAc 0.26 mmol) and triethylamine (3.4 L, 0.024 mmol) in N, N-dimethylacetamide (1.0 mL), and the mixture was stirred at 0 ° C for 42 hours. Ethyl acetate (1 ml), water (0.5 ml) and 20% aqueous ammonium chloride solution (0.5 ml) were added to the reaction mixture and vigorously stirred to separate the organic layer. The aqueous layer was extracted twice with ethyl acetate (1 ml each), and the organic layers were combined and washed three times with water (2.5 ml each). The obtained organic layer was concentrated under reduced pressure and purified from silica gel chromatography [heptane: ethyl acetate: triethylamine = 50: 50: 1 (v / v)] and dried under reduced pressure at 40 ° C to obtain the title compound and diastereomer The mixture (66.8 mg, yield 90%, diastereomer 84 (notation compound): 13: 3, optical purity 92% ee of the title compound) was obtained as an oily compound.

(HPLC conditions for optical purity measurement)

Column: CHIRALPAK IC 4.6 × 250 mm, 5 μm

Mobile layer: 0.1% HCOOH aq. : MeCN = 70: 30

Flow rate: 1.0 min / min

Column temperature: 27 ° C

Detection wavelength: 254 nm

Injection volume: 5 μl

Retention time: The indicated compound = 10.3 min, Enantiomer = 11.1 min

[Example 6]

(3'R, 4'S, 5'R) -6-chloro-4 '- (2-chloro-3-fluoropyridin- -3,3'-pyrrolidin-2 ', 4 "-pyran] -5'-carboxylate

(62)

(3E / Z) -6-chloro-3- [(2-chloro-3-fluoropyridin-4-yl) methylene] -1,3-dihydro-2H-indol- A mixture of tetrahydro-4H-pyran-4-one (prepared as described in WO-A-1212/121361) (48.7 mg, 0.16 mmol), (R) -BINAP (6.1 mg, 0.01 mmol), CuOAc (1.0 mg, 0.008 mmol) Was added a solution of N, N-dimethylacetamide (1.0 mL) of triethylamine (3.4 L, 0.024 mmol), glycine ethyl ester (20 L, 0.20 mmol) Lt; / RTI > for 42 hours. Ethyl acetate (1 ml), water (0.5 ml) and 20% aqueous ammonium chloride solution (0.5 ml) were added to the reaction mixture and vigorously stirred to separate the organic layer. The aqueous layer was extracted twice with ethyl acetate (1 ml each), and the organic layers were combined and washed three times with water (2.5 ml each). The obtained organic layer was concentrated under reduced pressure and purified from silica gel chromatography [heptane: ethyl acetate: triethylamine = 50: 50: 1 (v / v)] and dried under reduced pressure at 40 ° C to obtain the title compound and diastereomer (74.9 mg, yield 96%, diastereomer number 75 (notation compound): 20: 5, optical purity 98% ee of the title compound) as an oily compound.

(HPLC conditions for optical purity measurement)

Column: CHIRALPAK IC 4.6 × 250 mm, 5 μm

Mobile layer: 10 mM AcOH buffer: MeCN = 40: 60

Flow rate: 1.0 min / min

Column temperature: 27 ° C

Detected wavelength: 220 nm

Injection volume: 5 μl

Holding time: The stated compound = 26.2 min, Enantiomer = 22.8 min

[Example 7]

Ethyl 3 ', 4'S, 5'R) -6-chloro-4' - (2-chloro-3-fluoropyridin- 2-dihydrospiro [indole-3,3'-pyrrolidine] -5'-carboxylate

(63)

(3E / Z) -6-chloro-3- [(2-chloro-3-fluoropyridin-4-yl) methylene] -1,3-dihydro-2H-indol- Acetone (17.8 L, 0.24 mmol), glycine (0.24 mmol), and triethylamine were added to a mixture of (R) -BINAP (6.1 mg, 0.01 mmol) and CuOAc (1.0 mg, 0.008 mmol) N, N-dimethylacetamide (1.0 mL) solution of ethyl ester (20 L, 0.20 mmol) and triethylamine (3.4 L, 0.024 mmol) was added and the mixture was stirred at 0 ° C for 42 hours. Ethyl acetate (1 ml), water (0.5 ml) and 20% aqueous ammonium chloride solution (0.5 ml) were added to the reaction mixture and vigorously stirred to separate the organic layer. The aqueous layer was extracted twice with ethyl acetate (1 ml each), and the organic layers were combined and washed three times with water (2.5 ml each). The obtained organic layer was concentrated under reduced pressure and purified from silica gel chromatography [heptane: ethyl acetate: triethylamine = 50: 50: 1 (v / v)] and dried under reduced pressure at 40 ° C to obtain the title compound and diastereomer (68.9 mg, yield 92%, diastereomer number 87 (notation compound): 13, optical purity 98% ee of the title compound) as an oily compound.

(HPLC conditions for optical purity measurement)

Column: CHIRALPAK AS-RH 4.6 × 150 mm, 5 μm

Mobile layer: 10 mM AcOH buffer: MeCN = 60: 40

Flow rate: 1.0 min / min

Column temperature: 40 DEG C

Detection wavelength: 254 nm

Injection volume: 5 μl

Holding time: The indicated compound = 8.4 min, Enantiomer = 7.1 min

[Example 8]

(3'R, 4'S, 5'R) -6 "-chloro-4 '- (3-chloro-2-fluorophenyl) -2" Pyrrolo [cyclopentane-1,2'-pyrrolidin-3 ', 3 "-indole] -5'-carboxylate

≪ EMI ID =

(3E / Z) -6-chloro-3- (3-chloro-2-fluorobenzylidene) -1,3-dihydro-2H-indol- Cyclopentanone (28.7 쨉 L, 0.32 mmol), glycine ethyl ester (26.4 mg, 0.17 mmol) was added to a mixture of (R) -BINAP (6.1 mg, 0.01 mmol) and CuOAc N, N-dimethylacetamide (1.0 mL) of triethylamine (3.4 L, 0.024 mmol) was added to the solution, and the mixture was stirred at 0 ° C for 42 hours. Ethyl acetate (1 ml), water (0.5 ml) and 20% aqueous ammonium chloride solution (0.5 ml) were added to the reaction mixture and vigorously stirred to separate the organic layer. The aqueous layer was extracted twice with ethyl acetate (1 ml each), and the organic layers were combined and washed three times with water (2.5 ml each). The obtained organic layer was concentrated under reduced pressure and purified from silica gel chromatography [heptane: ethyl acetate: triethylamine = 100: 50: 1.5 (v / v)] and dried under reduced pressure at 40 ° C to obtain the title compound and diastereomer (69 mg, yield 86%, diastereomer 84 (the title compound): 14: 2, optical purity 99% ee of the title compound) as an oily compound.

(HPLC conditions for optical purity measurement)

Column: CHIRALPAK IC 4.6 × 250 mm, 5 μm

Mobile layer: 0.1% HCOOH aq. : MeCN = 50: 50

Flow rate: 1.0 min / min

Column temperature: 27 ° C

Detected wavelength: 220 nm

Injection volume: 5 μl

Retention time: The indicated compound = 6.0 min, Enantiomer = 5.6 min

[Example 9]

Chloro-4'- (2-chloro-3-fluoropyridin-4-yl) -2 " -oxo-1 ", 2 ' -Dihydrodipyrro [cyclopentane-l, 2'-pyrrolidin-3 ', 3 "-indole] -5'-carboxylate

(65)

(3E / Z) -6-chloro-3- [(2-chloro-3-fluoropyridin-4-yl) methylene] -1,3-dihydro-2H-indol- Cyclopentanone (21.6 L, 0.24 mmol) was added to a mixture of (R) -BINAP (6.1 mg, 0.01 mmol) and CuOAc (1.0 mg, 0.008 mmol) , N, N-dimethylacetamide (1.0 mL) of glycine ethyl ester (20 L, 0.20 mmol) and triethylamine (3.4 L, 0.024 mmol) was added and the mixture was stirred at 0 占 폚 for 42 hours. Ethyl acetate (1 ml), water (0.5 ml) and 20% aqueous ammonium chloride solution (0.5 ml) were added to the reaction mixture and vigorously stirred to separate the organic layer. The aqueous layer was extracted twice with ethyl acetate (1 ml each), and the organic layers were combined and washed three times with water (2.5 ml each). The obtained organic layer was concentrated under reduced pressure and purified from silica gel chromatography [heptane: ethyl acetate: triethylamine = 50: 50: 1 (v / v)] and dried under reduced pressure at 40 ° C to obtain the title compound and diastereomer The mixture (69.1 mg, yield 88%, diastereomer 87 (notation compound): 13, optical purity 98% ee of the title compound) was obtained as an oily compound.

(HPLC conditions for optical purity measurement)

Column: CHIRALPAK IC 4.6 × 250 mm, 5 μm

Mobile layer: 0.1% HCOOH aq. : MeCN = 50: 50

Flow rate: 1.0 min / min

Column temperature: 27 ° C

Detected wavelength: 220 nm

Injection volume: 5 μl

Holding time: The indicated compound = 6.7 min, Enantiomer = 13.3 min

[Example 10]

(3R, 4'S, 5'R) -N - [(3R, 6S) -6-carbamoyltetrahydro-2H- Chloro-3-fluoropyridin-4-yl) -4,4-dimethyl-2'-oxo-1 ", 2" -dihydrodipyrrolo [cyclohexane-1,2'-pyrrolidin- 3 ', 3 " -indole] -5 ' -carboxamide

(66)

[Step 1]

(4'S, 5'R) -6 "-chloro-4 '- (2-chloro-3-fluoropyridin- '- dihydrodipyrrolo [cyclohexane-1,2'-pyrrolidin-3', 3 "-indole] -5'-carboxylic acid

To a solution of the compound (5.00 g, 9.61 mmol) obtained in Example 4 in methanol (25 ml) and tetrahydrofuran (25 ml) was added 1N aqueous sodium hydroxide solution (18.3 ml, 18.3 mmol) under ice- , And the mixture was stirred at 0 ° C for 41.5 hours. The reaction mixture was ice-cooled, concentrated hydrochloric acid was added to neutralize the mixture to pH 3, water (75 ml) was added dropwise, and the mixture was stirred at room temperature for 4 hours. The precipitated solid was filtered at 0 占 폚 and dried under reduced pressure at 40 占 폚 to obtain the title compound (4.52 g, yield 96%) as a solid.

[Step 2]

(3R, 4'S, 5'R) -N - [(3R, 6S) -6-carbamoyltetrahydro-2H- Chloro-3-fluoropyridin-4-yl) -4,4-dimethyl-2'-oxo-1 ", 2" -dihydrodipyrrolo [cyclohexane-1,2'-pyrrolidin- 3 ', 3 " -indole] -5 ' -carboxamide

Hydroxybenzotriazole monohydrate (310 mg, 2.02 mmol), (2S, 4-benzyloxycarbonylamino) pyridine hydrochloride was added to a solution of the compound (2.00 g, 4.06 mmol) obtained in the above step 1 in N, N- 5R) -5-Aminotetrahydro-2H-pyran-2-carboxamide (WO2012 / 121361) (707 mg, 4.90 mmol), diisopropylethylamine (850 L, 4.88 mmol) 3- (3-dimethylaminopropyl) carbodiimide hydrochloride (934 mg, 4.87 mmol) was added and the mixture was stirred at 0 ° C for 47.5 hours. Ethyl acetate (20 mL) and water (10 mL) were added to the reaction mixture, and the organic layer was separated by stirring. The aqueous layer was extracted twice with ethyl acetate (20 mL each), and the organic layers were combined and washed three times with water (20 mL each). After the solvent was distilled off under reduced pressure, acetonitrile (30 ml) was added and the mixture was stirred at 60 캜 for 2 hours. After cooling, the precipitated solid was filtered and dried under reduced pressure at 40 캜 to obtain the title compound (2.13 g, yield 80%) as a solid.

[Example 11]

11-1) Influence by various sub catalysts

(67)

(3E / Z) -6-chloro-3- [(2-chloro-3-fluoropyridin-4-yl) methylene] -1,3-dihydro-2H-indol- To a THF solution (10 times) of 4,4-dimethylcyclohexanone (1.5 eq.), Glycine ethyl ester (1.2 eq.) And triethylamine (15 mol% (6 mol%), and THF (10 times) were stirred under nitrogen atmosphere for 1 hour, and the mixture was stirred at room temperature for 12 - 16 hours. Thereafter, the obtained trans1 compound ((ethyl (3'S, 4'R, 5'S) -6 '' - chloro-4 '- (2-chloro-3-fluoropyridin- -Dimethyl-2 " -oxo-1 ", 2 " -dihydrodipyrrolo [cyclohexane- 1,2 ' -pyrrolidin-3 & ) And the HPLC yield were measured.

(HPLC conditions for optical purity measurement)

Column: CHIRALPAK OD-3R 4.6 × 150 mm, 3 μm

Moving bed: 10 mM phosphate buffer: MeCN = 40: 60

Flow rate: 1.0 min / min

Column temperature: 40 DEG C

Detection wavelength: 254 nm

Injection volume: 5 μl

Holding time: The indicated compound = 13.8 min, Enantiomer = 12.9 min

The main results are shown in Table 1.

[Table 1-1]

[Table 1-2]

11-2) Influence by various solvents

(68)

(3E / Z) -6-chloro-3- [(2-chloro-3-fluoropyridin-4-yl) methylene] -1,3-dihydro-2H-indol- CuOAc (5 mol%) was added to 4,4-dimethylcyclohexanone (1.5 eq.), Glycine ethyl ester (1.2 eq.), Triethylamine (15 mol% ), (S) -BINAP (6 mol%) and a solvent (10 times) under nitrogen atmosphere for 1 hour, and the mixture was stirred at room temperature for 21.5 hours. Thereafter, the obtained trans2 compound (ethyl (3'S, 4'R, 5'S) -6 "-chloro-4 '- (2-chloro-3-fluoropyridin- Dimethyl-2 '' - oxo-1 '', 2 "-dihydrodipyrro [cyclohexane-1,2'-pyrrolidin-3 ', 3" -indole] -5'-carboxylate) Were measured for HPLC yield and optical purity.

The main results are shown in Table 2.

[Table 2]

11-3) Review of Cu (I) Lewis acid

(69)

(3E / Z) -6-chloro-3- [(2-chloro-3-fluoropyridin-4-yl) methylene] -1,3-dihydro-2H-indol- (1.5 eq.), Glycine ethyl ester (1.2 eq.), Triethylamine (15 mol%) and N, N-dimethylacetamide (10 times) Separately, the catalyst solution prepared by stirring Cu (I) Lewis acid (5 mol%), (S) -BINAP (6 mol%) and N, N-dimethylacetamide (10 times) in nitrogen atmosphere for 1 hour, The mixture was stirred at room temperature for 17-21.5 hours. Thereafter, the obtained trans2 compound (ethyl (3'S, 4'R, 5'S) -6 "-chloro-4 '- (2-chloro-3-fluoropyridin- Dimethyl-2 '' - oxo-1 '', 2 "-dihydrodipyrro [cyclohexane-1,2'-pyrrolidin-3 ', 3" -indole] -5'-carboxylate) Were measured for HPLC yield and optical purity.

Table 3 shows the main results.

[Table 3]

11-4) Review of Cu (II) Lewis Acid

(70)

(3E / Z) -6-chloro-3- [(2-chloro-3-fluoropyridin-4-yl) methylene] -1,3-dihydro-2H-indol- (R) -BINAP (6 mol%), 4-dimethylcyclohexanone (1.5 eq.), Glycine ethyl ester (1.2 eq.), Cu (II) , And N, N-dimethylacetamide (20-times volume) were stirred at room temperature for 15 hours under a nitrogen atmosphere. Thereafter, the obtained trans2 compound (ethyl (3'R, 4'S, 5'R) -6''-chloro-4 '- (2-chloro-3-fluoropyridin- 4'-dimethyl-2'-oxo-1 ", 2" -dihydrodipyrrolo [cyclohexane-1,2'-pyrrolidin-3 ', 3 "-indole] Rate) and optical purity by HPLC.

Table 4 shows the main results.

[Table 4]

* sign of ee: - signifies the trans 2 compound (ethyl (3'S, 4'R, 5'S) -6 "-chloro-4 '- (2-chloro-3-fluoropyridin- -Dimethyl-2 " -oxo-1 ", 2 " -dihydrodipyrrolo [cyclohexane- 1,2 ' -pyrrolidin-3 & ) Becomes the main product.

11-5) Examination using CuOAc and various subordinate ligands

(71)

(3E / Z) -6-chloro-3- [(2-chloro-3-fluoropyridin-4-yl) methylene] -1,3-dihydro-2H-indol- To a THF solution (10 times) of 4,4-dimethylcyclohexanone (1.5 eq.), Glycine ethyl ester (1.2 eq.) And triethylamine (15 mol%) was added CuOAc (6 mol%) and THF (10 times) under nitrogen atmosphere for 1 hour, and the mixture was stirred at room temperature for 12 to 16 hours. Thereafter, the trans 1 compound (ethyl (3'S, 4'R, 5'S) -6 "-chloro-4 '- (2-chloro-3-fluoropyridin- -2 '' - oxo-1 '', 2 "-dihydrodipyrro [cyclohexane-1,2'-pyrrolidin-3 ', 3" -indole] -5'-carboxylate Yield and optical purity were measured.

The main results are shown in Table 5.

[Table 5-1]

[Table 5-2]

[Table 5-3]

[Table 5-4]

* sign of ee: - signifies the trans 2 compound (ethyl (3'S, 4'R, 5'S) -6 "-chloro-4 '- (2-chloro-3-fluoropyridin- -Dimethyl-2 " -oxo-1 ", 2 " -dihydrodipyrrolo [cyclohexane- 1,2 ' -pyrrolidin-3 & ) Becomes the main product.

[Example 12]

chloro-4 '- (2-chloro-3-fluoropyridin-4-yl) -4,4- Oxo-1 ", 2" -dihydrodipyrro [cyclohexane-1,2'-pyrrolidin-3 ', 3 "-indole] -5'-carboxylate

(72)

(3E / Z) -6-chloro-3- [(2-chloro-3-fluoropyridin-4-yl) methylene] -1,3-dihydro-2H-indol- To a mixture of (R) -BINAP (6.0 mg, 0.009 mmol) and CuOAc (1.0 mg, 0.008 mmol) was added 4,4-dimethylcyclohexanone (31.0 mg N, N-dimethylacetamide (1.0 mL) of glycine tert-butyl ester (27.8 mg, 0.21 mmol) and triethylamine (3.4 L, 0.024 mmol) Lt; / RTI > for 19.5 hours. Ethyl acetate (2.0 ml), water (0.5 ml) and 20% aqueous ammonium chloride solution (0.5 ml) were added to the reaction mixture and vigorously stirred to separate the organic layer. The aqueous layer was extracted twice with ethyl acetate (2.0 mL each), and the organic layers were combined and washed three times with water (2.0 mL each). The obtained organic layer was concentrated under reduced pressure and purified from silica gel chromatography [heptane: ethyl acetate: triethylamine = 50: 50: 1 (v / v)] and dried under reduced pressure at 40 ° C to obtain the title compound and diastereomer (61.0 mg, yield 69%, diastereomer excess 90 (notation compound): 10, optical purity 97% ee of the title compound) as an oily compound.

(HPLC conditions for optical purity measurement)

Column: CHIRALPAK OD-3R 4.6 × 150 mm, 3 μm

Mobile layer: 0.1% (v / v) HCOOHaq. : MeCN = 50: 50

Flow rate: 1.0 ml / min

Column temperature: 40 DEG C

Detection wavelength: 254 nm

Injection volume: 5 μl

Holding time: The indicated compound = 9.4 min, Enantiomer = 11.4 min

[Referential Example 1]

(2S, 5R) -5 - [(2-aminoacetyl) amino] tetrahydro-2H-pyran-

(73)

[Step 1]

pyran-3-yl] amino} -2-oxoethyl) carbamate < / RTI >

(1.05 g, 5.77 mmol) and (2S, 5R) -5-aminotetrahydro-2H-pyran-2-carboxamide (WO2012 / 121361) (0.85 g, (7-azabenzotriazol-1-yl) -N, N, N-diisopropylcarbodiimide hydrochloride was added to a slurry of tetrahydrofuran (40 mL) of diisopropylethylamine (994 μL, 5.71 mmol) N ', N'-tetramethyluronium hexafluorophosphate (2.21 g, 5.83 mmol) was added, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure and purified from silica gel chromatography [ethyl acetate: methanol = 98: 2 → 80: 20 (v / v)]. Ethyl acetate (20 ml) was added to the obtained solid, and the mixture was stirred at room temperature for 4 hours. The obtained slurry was filtered and dried under reduced pressure at 40 ° C to obtain the title compound (1.47 g, yield 83%) as a white solid.

[Step 2]

(2S, 5R) -5 - [(2-aminoacetyl) amino] tetrahydro-2H-pyran-

To the compound (500 mg, 1.66 mmol) obtained in the above step 1, 4-hydrogen chloride / cyclopentyl methyl ether solution (5 ml, 20 mmol) was added and the mixture was stirred at room temperature for 15 hours. The reaction mixture was filtered and washed with cyclopentyl methyl ether (5 mL). A 28% sodium methoxide methanol solution (810 L, 3.32 mmol) was added to the obtained solid methanol (5 ml) solution, and the mixture was stirred at room temperature for 2 hours. Neutral silica gel (500 mg) was added to the reaction mixture obtained, and the mixture was concentrated under reduced pressure. Ethyl acetate (50 ml) and methanol (5 ml) were added and the silica gel was separated by filtration. The filtrate was concentrated under reduced pressure, tetrahydrofuran (2.0 ml) was added to the residue, and the mixture was stirred at room temperature for 17 hours. The resulting slurry was filtered and dried under reduced pressure at 40 ° C to obtain the title compound (111 mg, yield 33%) as a white solid.

[Example 13]

(3R, 4'S, 5'R) -N - [(3R, 6S) -6-carbamoyltetrahydro-2H- Chloro-3-fluoropyridin-4-yl) -4,4-dimethyl-2'-oxo-1 ", 2" -dihydrodipyrrolo [cyclohexane-1,2'-pyrrolidin- 3 ', 3 " -indole] -5 ' -carboxamide

≪ EMI ID =

(39.1 mg, 0.19 mmol), (3E / Z) -6-chloro-3- (3-chloro-2-fluorobenzylidene) -1,3-dihydro Was added to a mixture of 2-chloro-2H-indol-2-one (WO2006 / 091646) (48.6 mg, 0.16 mmol), (R) -BINAP (6.6 mg, 0.011 mmol), CuOAc (1.2 mg, 0.010 mmol) A solution of 4-dimethylcyclohexanone (30.6 mg, 0.24 mmol) in N, N-dimethylacetamide (1.0 mL) was added, and the mixture was stirred at room temperature for 17 hours. The whole amount of the reaction mixture was diluted with methanol (100 ml), and the title compound (ultra high velocity liquid chromatography (UHPLC) yield 65%, 96% de) was obtained as a methanol solution.

(UHPLC measurement conditions for UHPLC yield calculation)

Column: CAPCELL CORE ADME 2.1 x 100 mm, 2.7 μm

Mobile layer: 0.1% (v / v) HCOOHaq. : MeCN

Gradient: MeCN 20% to 92%

Gradient conditions: 0 - 2.5 min MeCN 20%, 2.5 - 7.3 min MeCN 20 → 92%, 7.3 - 14 min MeCN 92%, 14.01 - 17 min MeCN 20%

Flow rate: 0.6 ml / min

Column temperature: 40 DEG C

Detection wavelength: 254 nm

Injection volume: 5 μl

Holding time: The term compound is 6.6 min

(HPLC conditions for de measuring)

Column: CHIRALPAK OD-3R 4.6 × 150 mm, 3 μm

Mobile layer: 0.1% (v / v) HCOOHaq. : MeCN = 60: 40

Flow rate: 1.0 ml / min

Column temperature: 40 DEG C

Detection wavelength: 254 nm

Injection volume: 10 μl

Holding time: The indicated compound = 17.7 min, Diastereomer = 8.5 min

[Example 14]

(Trans-4-hydroxycyclohexyl) -2 " - (3-chloro-2-fluorophenyl) Oxo-1 ", 2" -dihydrodipyrro [cyclohexane-1,2'-pyrrolidin-3 ', 3 "-indole] -5'-carboxamide

(75)

[Step 1]

(Trans-4-hydroxycyclohexyl) -2 ' -oxo-1 ' ', 2'-dihydrodipyrrolo [cyclohexane-1,2'-pyrrolidin-3', 3 "-indole] -5"

An aqueous sodium hydroxide solution (1.0 ml, 6.25 mmol) was added under ice-cooling to a slurry of the compound (1.00 g, 2.04 mmol) obtained in Example 1 and methanol (10 ml) Followed by stirring at 0 ° C for 27.5 hours. To the reaction mixture was added an aqueous solution of 35% (w / w) concentrated hydrochloric acid (651 mg, 6.25 mmol) under ice-cooling, neutralized, and water (15 mL) was added thereto, followed by stirring at 0 ° C for 18 hours. The precipitated crystals were filtered at 0 ° C and dried under reduced pressure at 40 ° C to obtain the title compound (0.90 g, yield 95%,> 99.5% ee) as a pale yellow solid.

(HPLC conditions for optical purity measurement)

Column: CHIRALPAK QN-AX 4.6 × 150 mm, 3 μm

Mobile layer: 0.1% (v / v) HCOOHaq. : MeCN = 60: 40

Flow rate: 1.0 ml / min

Column temperature: 40 DEG C

Detection wavelength: 254 nm

Injection volume: 5 μl

Retention time: The indicated compound = 7.5 min, Enantiomer = 4.0 min

[Step 2]

(Trans-4-hydroxycyclohexyl) -2 " - (3-chloro-2-fluorophenyl) Oxo-1 ", 2" -dihydrodipyrro [cyclohexane-1,2'-pyrrolidin-3 ', 3 "-indole] -5'-carboxamide

To a solution of the compound obtained in the above step 1 (501 mg, 1.08 mmol, 99% ee) and trans-4-aminocyclohexanol (157 mg, 1.36 mmol) in N, N- dimethylacetamide (5 mL) (392 mg, 1.42 mmol) was added to a stirred solution of 4 (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride Lt; / RTI > Ethyl acetate (10 mL) and water (5 mL) were added to the reaction mixture, and the organic layer was separated by stirring. The aqueous layer was extracted with ethyl acetate (10 ml), and the organic layers were combined and washed three times with water (10 ml each). After the solvent was distilled off under reduced pressure, acetonitrile (15 ml) was added and the mixture was stirred at room temperature for 18 hours. The precipitated crystals were filtered and dried under reduced pressure at 40 ° C to obtain the title compound (426 g, yield 70%,> 99.5% ee) as a white solid.

(HPLC conditions for optical purity measurement)

Column: CHIRALPAK OD-3R 4.6 × 150 mm, 3 μm

Mobile layer: 0.1% (v / v) HCOOHaq. : MeCN = 60: 40

Flow rate: 1.0 ml / min

Column temperature: 40 DEG C

Detection wavelength: 254 nm

Injection volume: 5 μl

Retention time: The indicated compound = 4.9 min, Enantiomer = 4.2 min

Claims (20)

A compound represented by formula (I):
[Chemical Formula 1]

A compound represented by formula (II):
(2)

And a compound represented by the formula (III):
(3)

Are reacted in a solvent using an asymmetric catalyst,
The compound represented by the formula (IV) or a salt thereof:
[Chemical Formula 4]

≪ / RTI >
[Of the formulas (I), (II), (III) and (IV)
R ¹ represents a hydrogen atom, a C ₁ -C ₆ alkylcarbonyl group which may have 1 to 3 substituents independently selected from the following group A, a C ₁ -C ₆ alkylcarbonyl group which may have 1 to 3 substituents independently selected from the following group A ₁ -C ₆ alkoxy group,
R ² represents a 5- or 6-membered heteroaryl group having 1 to 3 hetero atoms independently selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, a phenyl group, a C ₃ -C ₆ cycloalkyl group, or A C ₃ -C ₆ cycloalkenyl group,
The 5-atom or 6-atom heteroaryl group, the phenyl group, the C ₃ -C ₆ cycloalkyl group, and the C ₃ -C ₆ cycloalkenyl group may be substituted with a halogen atom, a vinyl group, an ethynyl group, a cyano group, a hydroxyl group , An amino group, a carboxyl group, an aminocarbonyl group, a C ₁ -C ₆ alkyl group which may have 1 to 3 substituents independently selected from the following A group, a C ₁ -C ₆ alkyl group which may have 1 to 3 substituents independently selected from the following A group ₃ -C ₄ cycloalkyl group, to which optionally a substituent selected independently have one of 1 to 3 in the a group C ₁ -C ₆ alkoxy group, C which may have to be 1 to 3 substituents selected independently one from the group a _A C ₃ -C ₄ cycloalkoxy group, a C ₁ -C ₆ alkylamino group which may have 1 to 3 substituents independently selected from the following group A, 1 to 3 substituents independently selected from the following group A A C ₁ -C ₆ alkylamino group which may be substituted, a saturated heterocyclic group of 4 to 7 atoms containing one nitrogen atom in the ring, which may have 1 to 3 substituents independently selected from the following group B, A C ₁ -C ₆ alkoxycarbonyl group which may have 1 to 3 substituents independently selected from the following group A, a C ₃ -C ₄ cycloalkoxycarbonyl group which may have 1 to 3 substituents independently selected from the following A group , A C ₁ -C ₆ alkylaminocarbonyl group which may have 1 to 3 substituents independently selected from the following group A, and C ₃ -C ₄ alkylcarbonyl optionally having 1 to 3 substituents independently selected from the group A May have 1 to 3 substituents independently selected from the group consisting of a cycloalkylaminocarbonyl group,
R ³ and R ⁴ each independently represent a C ₁ -C ₆ alkyl group which may have 1 to 3 substituents independently selected from the following group C, or
R ³ and R ⁴ may be combined to form a C ₄ -C ₆ cycloalkyl ring, a tetrahydrofuran ring, a tetrahydropyran ring, or a piperidine ring,
The C ₄ -C ₆ cycloalkyl ring, the tetrahydrofuran ring, the tetrahydropyran ring and the piperidine ring thereof may have 1 to 8 substituents independently selected from the following group D,
R ⁵ is a C ₁ -C ₆ alkoxy group which may have 1 to 3 substituents independently selected from the following group E, a C ₃ -C ₈ alkoxy group which may have 1 to 3 substituents independently selected from the following E group A cycloalkoxy group, a C ₂ -C ₆ alkenyloxy group, or -NR ⁵¹ R ⁵² ,
R ⁵¹ and R ⁵² each independently represent a hydrogen atom, a C ₁ -C ₆ alkyl group which may have 1 to 3 substituents independently selected from the following E group, 1 to 3 substituents independently selected from the following E group A C ₃ -C ₈ cycloalkyl group which may be present, or a hetero atom independently selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, which may have 1 to 3 substituents independently selected from the group E below, A saturated heterocyclic group having 3 to 6 atoms,
The ring Z is a benzene ring which may have 1 to 4 substituents independently selected from the following E group, a pyridine ring which may have 1 to 3 substituents independently selected from the following E group, Or a pyrimidine ring which may have 1 or 2 substituents selected from [
Group A: a halogen atom, a hydroxyl group, a C ₁ -C ₆ alkyl group, an amino group, a phenyl group
Group B: a C ₁ -C ₆ alkyl group, a hydroxyl group
Group C: a halogen atom, a hydroxyl group, a phenyl group, a pyridyl group,
Group D: a halogen atom, a C ₁ -C ₆ alkyl group optionally having 1 to 3 halogen atoms,
Group E: a halogen atom, a hydroxyl group, a vinyl group, an ethynyl group, a cyano group, C ₁ -C ₆ alkoxy group, an amino group, a halogen atom, a C ₁ -C ₆ alkyl group which may have one 1-3 A compound represented by formula (I):
[Chemical Formula 5]

And a compound represented by the formula (V):
[Chemical Formula 6]

Are reacted in a solvent using an asymmetric catalyst,
The compound represented by the formula (IV) or a salt thereof:
(7)

≪ / RTI >
Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and Z have the same meanings as defined in claim 1, 3. The method according to claim 1 or 2,
A catalyst in which an asymmetric catalyst is prepared from a Lewis acid and an aldehyde ligand,
(II) Lewis acid, Cu (I) Lewis acid, Cu (I) Lewis acid, Cu (II) ) ≪ / RTI > Lewis acid,
The sub-ligand has the following formula (VI):
[Chemical Formula 8]

A compound represented by the following formula (VII):
[Chemical Formula 9]

A compound represented by the following formula (VIII):
[Chemical formula 10]

A compound represented by the following formula (IX):
(11)

A compound represented by the following formula (X):
[Chemical Formula 12]

A compound represented by the following formula (XI):
[Chemical Formula 13]

And a compound represented by the following formula (XII):
[Chemical Formula 14]

Wherein the ligand is one kind of an asymmetric ligand.
Among the formulas (VI), (VII), (VIII), (IX), (X), (XI)
R ⁶ represents a phenyl group which may have 1 to 3 substituents independently selected from the following group F,
The ring Y represents a benzene ring, a cyclohexane ring, or a dioxolane ring which may have 1 to 4 halogen atoms,
R ⁷ represents a phenyl group which may have 1 to 3 substituents independently selected from the following G groups or a furanyl group which may have 1 to 3 substituents independently selected from the group G below,
R ⁸ represents a hydrogen atom or a C ₁ -C ₆ alkoxy group,
R ⁹ represents a C ₁ -C ₆ alkoxy group, or
Two R ^{9 s} may be one to form a heterocyclic ring of 7 to 12 atoms containing two oxygen atoms in the ring,
X represents CH, CR < ¹⁰ > or a nitrogen atom,
R ¹⁰ represents a C ₁ -C ₆ alkoxy group,
V represents a phenyl group having one of P (R ¹¹ ) ₂ , PH (O) R ¹² , or P (R ¹¹ ) ₂ ,
R ¹¹ represents a C ₁ -C ₆ alkyl group, a cyclohexyl group, or a phenyl group which may have two trifluoromethyl groups,
R ¹² represents a C ₁ -C ₆ alkyl group or a phenyl group,
W represents a C ₁ -C ₆ alkylthio group, a dihydrooxazolyl group which may have one C ₁ -C ₆ alkyl group, CH (CH ₃ ) P (R ¹³ ) ₂ , or CHR ¹⁴ R ¹⁵ ,
R ¹³ represents a cyclohexyl group, a C ₁ -C ₆ alkyl group, or a phenyl group which may have 1 or 2 substituents independently selected from the group H below,
R ¹⁴ represents a phenyl group which may be substituted with one of P (R ¹⁶ ) ₂ ,
R ¹⁵ represents a C ₁ -C ₆ alkyl group or a di C ₁ -C ₆ alkylamino group,
R ¹⁶ represents a phenyl group or a cyclohexyl group,
U is to represents any one of ^a U to U ^d dog,
[Chemical Formula 15]

R ¹⁷ represents a phenyl group which may have 1 to 3 substituents independently selected from the following group F,
R ¹⁸ represents a C ₁ -C ₆ alkyl group or a phenyl group,
R ¹⁹ represents a hydrogen atom or a C ₁ -C ₆ alkyl group,
R ²⁰ and R ²¹ each independently represent a C ₁ -C ₆ alkyl group]
F group: a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group
G group: a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group, a di C ₁ -C ₆ alkylamino group
H group: a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkyl group which may have 3 halogen atoms 4. The method according to any one of claims 1 to 3,
Wherein the Lewis acid used in the preparation of the sub catalyst is Cu (I) Lewis acid or Cu (II) Lewis acid. 5. The method according to any one of claims 1 to 4,
One kind of acid is Lewis used in the preparation of the asymmetric catalyst, selected from the CuOAc, CuCl, CuBr, CuI, CuOTf, CuPF _6, CuBF _4, the group consisting of _{Cu (OAc) 2, Cu (} OTf) 2, and CuSO ₄ Lewis acid. 6. The method according to any one of claims 1 to 5,
(V), the compound represented by the formula (VI), the compound represented by the formula (VII), the compound represented by the formula (VIII), the compound represented by the formula (IX), a compound represented by the formula (X), and a compound represented by the formula (XI).
Among the formulas (V), (VI), (VII), (VIII), (IX), (X) and (XI)
R ⁶ represents a phenyl group which may have 1 to 3 substituents independently selected from the group consisting of a methyl group, a t-butyl group and a methoxy group,
The ring Y represents a benzene ring, a cyclohexane ring or a dioxolane ring,
R ⁷ represents a phenyl group or a furanyl group,
The phenyl group and the furanyl group may have 1 to 3 substituents independently selected from the group consisting of a methyl group, a t-butyl group, and a methoxy group,
R ⁸ represents a hydrogen atom or a methoxy group,
R ⁹ represents a methoxy group, or
Two R ^{9 s} may be one to form a 9-membered heterocyclic ring containing 2 oxygen atoms in the ring,
X represents CH, CR < ¹⁰ > or a nitrogen atom,
R < ¹⁰ > represents a methoxy group,
V represents P (R < ¹¹ >) ₂ ,
R ¹¹ represents a phenyl group which may have two trifluoromethyl groups,
W represents a dihydrooxazolyl group which may be substituted by a t-butylthio group, an isopropyl group, or CH (CH ₃ ) P (R ¹³ ) ₂ ,
R ¹³ represents a phenyl group which may have 1 or 2 methyl groups,
U represents U ^a or U ^d ,
R ¹⁷ represents a phenyl group,
R ¹⁸ represents an isopropyl group, a t-butyl group, or a phenyl group,
R < ¹⁹ > represents a hydrogen atom,
R ²⁰ and R ²¹ each independently represents a methyl group or a t-butyl group] 7. The method according to any one of claims 1 to 6,
Wherein the subtitle ligand used in the preparation of the subtitle catalyst is one of the subtitle ligands selected from the following.
[Chemical Formula 16]

[Chemical Formula 17]

8. The method according to any one of claims 1 to 7,
Wherein the solvent used in the reaction is one or a plurality of solvents selected from the group consisting of N, N-dimethylacetamide, tetrahydrofuran, dimethoxyethane, 2-propanol, toluene, and ethyl acetate. 9. The method according to any one of claims 1 to 8,
Wherein the compound to be produced or a salt thereof has the following configuration.
[Chemical Formula 18]

Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and Z have the same meanings as defined in claim 1, 10. The method according to any one of claims 1 to 9,
Wherein R < ¹ > is a hydrogen atom. 11. The method according to any one of claims 1 to 10,
In the above formula (I)
And the ring Z is a benzene ring which may have 1 to 4 halogen atoms. 12. The method according to any one of claims 1 to 11,
In the formula (II) or the formula (V)
R ² is a pyridyl group which may have 1 to 4 halogen atoms or a phenyl group which may have 1 to 5 halogen atoms. 13. The method according to any one of claims 1 to 12,
In the formula (II) or the formula (V)
R ³ and R ⁴ each represent a methyl group, or R ³ and R ⁴ are combined to form a cyclopentane ring, a cyclohexane ring or a tetrahydropyran ring,
Wherein the cyclopentane ring, the cyclohexane ring, and the tetrahydropyran ring thereof may have 1 to 4 C ₁ -C ₆ alkyl groups on the ring. 14. The method according to any one of claims 1 to 13,
In the formula (III) or the formula (V)
Wherein R < ⁵ > is a substituent shown below,
[Chemical Formula 19]

Gt; 14. The method according to any one of claims 1 to 13,
In the formula (III) or the formula (V)
R ⁵ is C ₁ -C ₆ alkoxy group method. A compound or a salt thereof produced by the production method according to claim 15,
To obtain a compound represented by the following formula (XIV) or a salt thereof:
[Chemical Formula 20]

And condensing the compound represented by NHR ²² R ²³ to obtain a compound represented by the following formula (XV) or a salt thereof:
[Chemical Formula 21]

≪ / RTI >
[Of the formulas (XIV) and (XV)
R ¹ , R ² , R ³ , R ⁴ , and Z have the same meanings as defined in any one of claims 1 to 13,
R ²² and R ²³ each independently represent a hydrogen atom, a C ₁ -C ₆ alkyl group which may have 1 to 3 substituents independently selected from the following Group I, 1 to 3 substituents independently selected from the following Group I A C ₁ -C ₆ alkylsulfonyl group which may be substituted, a C ₃ -C ₆ cycloalkyl group which may have 1 to 3 substituents independently selected from the following Group I, a substituent independently selected from the following Group I, A saturated heterocyclic group of 3 to 6 atoms having one hetero atom independently selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, which may be present in the ring, a substituent independently selected from the following Group I, A phenyl group which may have 1 to 3 substituents or a nitrogen atom which may have 1 to 3 substituents independently selected from the following Group I, And a sulfur atom, or a 5- or 6-membered heteroaryl group having 1 to 3 hetero atoms in the ring, or
R ²² and R ²³ may be combined to form a piperazine ring which may have 1 to 3 substituents independently selected from the following Group I]
Group I: a halogen atom, hydroxyl group, oxo group, carboxyl group, formyl group, amino group, amino group, cyano group, C ₁ -C ₆ alkylamino group, C ₁ -C ₆ alkylsulfonyl group, C ₁ -C ₆ alkylsulfonyl sulfonyl amide group, to C ₁ -C ₆ which may optionally have 1 to 3 substituents independently selected more C ₁ -C ₆ alkyl group, 1 to 3 have the substituents independently selected from the group J in the J group alkoxy group, a -C ₃ to C ₆ which may optionally have a substituent selected independently from one 1 to 3 C ₁ -C ₆ alkyl with from 1 to 3 substituents selected independently one from the group, to the group J in the J group A cycloalkylcarbonyl group, a C ₄ -C ₆ cycloalkyl group which may have 1 to 3 substituents independently selected from the following group J, a cycloalkyl group which may have 1 to 3 substituents independently selected from the following group J A C ₁ -C ₆ alkoxycarbonyl group, a piperidinyl group optionally having 1 to 3 substituents independently selected from the following group J, a pyrrolidinyl group optionally having 1 to 3 substituents independently selected from the following group J , A piperazinyl group optionally having 1 to 3 substituents independently selected from the following group J, a phenyl group or a tetrazolyl group optionally having 1 to 3 substituents independently selected from the following group J, An azetidinyl group which may have 1 to 3 substituents independently selected, a morpholino group which may optionally have 1 to 3 substituents independently selected from the following group J, a substituent independently selected from the following group J, A dihydropyrazolyl group which may have 3 or more oxadiazolyl groups
J group: a halogen atom, a hydroxyl group, an amino group, a carboxyl group, an aminocarbonyl group, a phenyl group, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkylamino group, a di C ₁ -C ₆ alkylamino group, a C ₁ -C ₆ alkylcarbonyl group , A C ₃ -C ₆ cycloalkyl group, a C ₁ -C ₆ alkylsulfonyl group, a C ₁ -C ₆ alkylsulfonylamide group 17. The method of claim 16,
R ²² represents a hydrogen atom,
R < ²³ > is a substituent shown below,
[Chemical Formula 22]

Gt; The compound represented by the formula (XVI):
(23)

The compound represented by the formula (XVII):
≪ EMI ID =

And (XVIII): < EMI ID =
(25)

In a solvent:
Cu (I) Lewis acid, and Cu (II) Lewis acid, and a subgenus ligand selected from the following:
(26)

(27)

, ≪ / RTI >
The compound represented by the formula (XIX) or a salt thereof:
(28)

≪ / RTI >
[Of the formulas (XVI), (XVII), (XVIII) and (XIX)
M represents a nitrogen atom or CH,
L represents a single bond, an oxygen atom, CH ₂ or C (CH ₃ ) ₂ ,
R ⁵³ represents a C ₁ -C ₆ alkyl group] The compound represented by the formula (XVI):
[Chemical Formula 29]

And the compound represented by the formula (XX):
(30)

In a solvent:
Cu (I) Lewis acid, and Cu (II) Lewis acid, and a subgenus ligand selected from the following:
(31)

(32)

, ≪ / RTI >
The compound represented by the formula (XIX) or a salt thereof:
(33)

≪ / RTI >
[Of the formulas (XVI), (XX), and (XIX)
M, L and R ⁵³ have the same meanings as defined in claim 19] 19. A method for producing a compound or a salt thereof, which comprises using a compound according to claim 18 or 19,
To obtain a compound represented by the following formula (XXI) or a salt thereof:
(34)

And the following compounds:
(35)

To obtain a compound represented by the following formula (XXII) or a salt thereof:
(36)

≪ / RTI >
[Of the formulas (XXI) and (XXII)
M and L have the same meanings as defined in claim 18 or 19]